bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023‒07‒02
forty-four papers selected by
Dylan Ryan
University of Cambridge
  1. Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.
  2. Distinct metabolic requirements regulate B cell activation and germinal center responses.
  3. Spns2/S1P: it takes two to tango with inflammation and metabolic rewiring during sepsis.
  4. Enhancing Spns2/S1P in macrophages alleviates hyperinflammation and prevents immunosuppression in sepsis.
  5. Gut microbial fatty acid isomerization modulates intraepithelial T cells.
  6. CD26 CAR-T Cells Have Attenuated Mitochondrial and Glycolytic Metabolic Profiling.
  7. Immunometabolism and immune response regulate macrophage function in atherosclerosis.
  8. Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy.
  9. The interplay between microbial metabolites and macrophages in cardiovascular diseases: A comprehensive review.
  10. Trehalose Inhibits Inflammatory Responses through Mitochondrial Reprogramming in RAW 264.7 Macrophages.
  11. Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring.
  12. Serendipitous Discovery of T Cell-Produced KLK1b22 as a Regulator of Systemic Metabolism.
  13. IL-27 enhances peripheral B cell glycolysis of rheumatoid arthritis patients via activating mTOR signaling.
  14. Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviates atherosclerosis through the modulation of M1 polarization.
  15. LACC1: A critical involvement in macrophage immunometabolism.
  16. Propofol inhibits neuroinflammation and metabolic reprogramming in microglia in vitro and in vivo.
  17. Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.
  18. Hypoxia-altered cholesterol homeostasis enhances the expression of interferon-stimulated genes upon SARS-CoV-2 infections in monocytes.
  19. A Scoping Review on the Effects of Physical Exercise and Fitness on Peripheral Leukocyte Energy Metabolism in Humans.
  20. Metabolic Adaption of Mucosal Macrophages: Is Metabolism a Driver of Persistence Across Tissues?
  21. Intrahepatic macrophage reprogramming associated with lipid metabolism in hepatitis B virus-related acute-on-chronic liver failure.
  22. Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.
  23. The Regulation Network of Glycerolipid Metabolism as Coregulators of Immunotherapy-Related Myocarditis.
  24. Oxylipin secretion by human CD3+ T lymphocytes in vitro is modified by the exogenous essential fatty acid ratio and life stage.
  25. Niclosamide inhibits Newcastle disease virus replication in chickens by perturbing the cellular glycolysis.
  26. Metabolomics and Machine Learning Identify Metabolic Differences and Potential Biomarkers for Frequent versus Infrequent Gout Flares.
  27. Apilimod activates the NLRP3 inflammasome through lysosome-mediated mitochondrial damage.
  28. Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation.
  29. The anti-inflammatory and bioregulatory effects of habitual exercise in high-fat diet-induced obesity involve crown-like structures and MCP-1 in white adipose tissue.
  30. Inhibition of the Mitochondrial Carnitine/Acylcarnitine Carrier by Itaconate through Irreversible Binding to Cysteine 136: Possible Pathophysiological Implications.
  31. S1P/S1PR1 axis promotes macrophage M1 polarization through NLRP3 inflammasome activation in Lupus nephritis.
  32. Differential Lipidomics, Metabolomics and Immunological Analysis of Alcoholic and Non-Alcoholic Steatohepatitis in Mice.
  33. Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy.
  34. The Effects of Mitochondrial Transplantation on Sepsis Depend on the Type of Cell from Which They Are Isolated.
  35. Ultrasound-responsive low-dose doxorubicin liposomes trigger mitochondrial DNA release and activate cGAS-STING-mediated antitumour immunity.
  36. How Bacterial Pathogens Coordinate Appetite with Virulence.
  37. Parabacteroides distasonis uses dietary inulin to suppress NASH via its metabolite pentadecanoic acid.
  38. JPH203, a LAT1 inhibitor, alleviates steroid-resistant murine airway inflammation mediated by Th17 cells.
  39. Adenylosuccinic Acid: An Orphan Drug with Untapped Potential.
  40. A back-door insights into the modulation of Src kinase activity by the polyamine spermidine.
  41. Effect of hyperglycemia on the immune function of COVID-19 patients with type 2 diabetes mellitus: a retrospective study.
  42. Single cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome.
  43. Transcriptome-guided metabolic network analysis reveals rearrangements of carbon flux distribution in Neisseria gonorrhoeae during neutrophil co-culture.
  44. Glycolytic enzyme HK2 promotes PD-L1 expression and breast cancer cell immune evasion.
  1. Science. 2023 Jun 30. 380(6652): 1372-1380
    Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.
    Tao Zhang, Daichao Xu, Elijah Trefts, Mingming Lv, Hiroyuki Inuzuka, Guobin Song, Min Liu, Jianlin Lu, Jianping Liu, Chen Chu, Min Wang, Huibing Wang, Huyan Meng, Hui Liu, Yuan Zhuang, Xingxing Xie, Fabin Dang, Dongxian Guan, Yuqin Men, Shuwen Jiang, Cong Jiang, Xiaoming Dai, Jing Liu, Zhen Wang, Peiqiang Yan, Jingchao Wang, Zhenbo Tu, Mrigya Babuta, Emily Erickson, Alissandra L Hillis, Christian C Dibble, John M Asara, Gyongy Szabo, Piotr Sicinski, Ji Miao, Yu-Ru Lee, Lifeng Pan, Reuben J Shaw, Junying Yuan, Wenyi Wei.
      Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.
    DOI:  https://doi.org/10.1126/science.abn1725
  2. Nat Immunol. 2023 Jun 26.
    Distinct metabolic requirements regulate B cell activation and germinal center responses.
    Rahul Sharma, Ryan M Smolkin, Priyanka Chowdhury, Keith Conrad Fernandez, Youngjun Kim, Montserrat Cols, William Alread, Wei-Feng Yen, Wei Hu, Zhong-Min Wang, Sara Violante, Ronan Chaligné, Ming O Li, Justin R Cross, Jayanta Chaudhuri.
      Following infection or vaccination, activated B cells at extrafollicular sites or within germinal centers (GCs) undergo vigorous clonal proliferation. Proliferating lymphocytes have been shown to undertake lactate dehydrogenase A (LDHA)-dependent aerobic glycolysis; however, the specific role of this metabolic pathway in a B cell transitioning from a naïve to a highly proliferative, activated state remains poorly defined. Here, we deleted LDHA in a stage-specific and cell-specific manner. We find that ablation of LDHA in a naïve B cell did not profoundly affect its ability to undergo a bacterial lipopolysaccharide-induced extrafollicular B cell response. On the other hand, LDHA-deleted naïve B cells had a severe defect in their capacities to form GCs and mount GC-dependent antibody responses. In addition, loss of LDHA in T cells severely compromised B cell-dependent immune responses. Strikingly, when LDHA was deleted in activated, as opposed to naïve, B cells, there were only minimal effects on the GC reaction and in the generation of high-affinity antibodies. These findings strongly suggest that naïve and activated B cells have distinct metabolic requirements that are further regulated by niche and cellular interactions.
    DOI:  https://doi.org/10.1038/s41590-023-01540-y
  3. EMBO Rep. 2023 Jun 26. e57615
    Spns2/S1P: it takes two to tango with inflammation and metabolic rewiring during sepsis.
    Tineke Vanderhaeghen, Jolien Vandewalle, Claude Libert.
      Sepsis is the result of a dysregulated host response to an infection and causes high morbidity and mortality at the intensive care units worldwide. Despite intensive research, the current management of sepsis is supportive rather than curative. Therefore, new therapeutic interventions for sepsis and septic shock patients are urgently needed. In this issue of EMBO Reports, Fang et al have used rat sepsis models to show that macrophage-expressed SPNS2, a major transporter of S1P, is a crucial mediator of metabolic reprogramming of macrophages during sepsis which regulates inflammation via the lactate-ROS axis.
    DOI:  https://doi.org/10.15252/embr.202357615
  4. EMBO Rep. 2023 Jun 26. e56635
    Enhancing Spns2/S1P in macrophages alleviates hyperinflammation and prevents immunosuppression in sepsis.
    Chao Fang, Pan Ren, Ganlan Bian, Jian Wang, Jiaxin Bai, Jiaxing Huang, Yixiao Ding, Xueyong Li, Mingkai Li, Zheng Hou.
      Sepsis is a leading cause of in-hospital mortality resulting from a dysregulated response to infection. Novel immunomodulatory therapies targeting macrophage metabolism have emerged as an important focus for current sepsis research. However, understanding the mechanisms underlying macrophage metabolic reprogramming and how they impact immune response requires further investigation. Here, we identify macrophage-expressed Spinster homolog 2 (Spns2), a major transporter of sphingosine-1-phosphate (S1P), as a crucial metabolic mediator that regulates inflammation through the lactate-reactive oxygen species (ROS) axis. Spns2 deficiency in macrophages significantly enhances glycolysis, thereby increasing intracellular lactate production. As a key effector, intracellular lactate promotes pro-inflammatory response by increasing ROS generation. The overactivity of the lactate-ROS axis drives lethal hyperinflammation during the early phase of sepsis. Furthermore, diminished Spns2/S1P signaling impairs the ability of macrophages to sustain an antibacterial response, leading to significant innate immunosuppression in the late stage of infection. Notably, reinforcing Spns2/S1P signaling contributes to balancing the immune response during sepsis, preventing both early hyperinflammation and later immunosuppression, making it a promising therapeutic target for sepsis.
    Keywords:  Spinster homolog 2; immunomodulation; macrophages; sepsis; sphingosine-1-phosphate
    DOI:  https://doi.org/10.15252/embr.202256635
  5. Nature. 2023 Jun 28.
    Gut microbial fatty acid isomerization modulates intraepithelial T cells.
    Xinyang Song, Haohao Zhang, Yanbo Zhang, Byoungsook Goh, Bin Bao, Suelen S Mello, Ximei Sun, Wen Zheng, Francesca S Gazzaniga, Meng Wu, Fangfang Qu, Qiangzong Yin, Michael S Gilmore, Sungwhan F Oh, Dennis L Kasper.
      The human gut microbiome constantly converts natural products derived from the host and diet into numerous bioactive metabolites1-3. Dietary fats are essential micronutrients that undergo lipolysis to release free fatty acids (FAs) for absorption in the small intestine4. Gut commensal bacteria modify some unsaturated FAs-for example, linoleic acid (LA)-into various intestinal FA isomers that regulate host metabolism and have anticarcinogenic properties5. However, little is known about how this diet-microorganism FA isomerization network affects the mucosal immune system of the host. Here we report that both dietary factors and microbial factors influence the level of gut LA isomers (conjugated LAs (CLAs)) and that CLAs in turn modulate a distinct population of CD4+ intraepithelial lymphocytes (IELs) that express CD8αα in the small intestine. Genetic abolition of FA isomerization pathways in individual gut symbionts significantly decreases the number of CD4+CD8αα+ IELs in gnotobiotic mice. Restoration of CLAs increases CD4+CD8αα+ IEL levels in the presence of the transcription factor hepatocyte nuclear factor 4γ (HNF4γ). Mechanistically, HNF4γ facilitates CD4+CD8αα+ IEL development by modulating interleukin-18 signalling. In mice, specific deletion of HNF4γ in T cells leads to early mortality from infection by intestinal pathogens. Our data reveal a new role for bacterial FA metabolic pathways in the control of host intraepithelial immunological homeostasis by modulating the relative number of CD4+ T cells that were CD4+CD8αα+.
    DOI:  https://doi.org/10.1038/s41586-023-06265-4
  6. Immunopharmacol Immunotoxicol. 2023 Jun 29. 1-12
    CD26 CAR-T Cells Have Attenuated Mitochondrial and Glycolytic Metabolic Profiling.
    Xiaoying Zhu, Zhaodong Zhong, Fankai Meng, Ping Zou, Yong You, Qing Li, Xiaojian Zhu.
      BACKGROUND: Multiple targets of chimeric antigen receptor T cells (CAR-T cells) are shared expressed by tumor cells and T cells, these self antigens may stimulate CAR-T cells continuously during the expansion. Persistent exposure to antigens is considered to cause metabolic reprogramming of T cells and the metabolic profiling is critical in determining the cell fate and effector function of CAR-T cells. However, whether self-antigen stimulation during CAR-T cell generation could remodel the metabolic profiling is unclear. In this study, we aim to investigate the metabolic characteristics of CD26 CAR-T cells, which expressed CD26 antigens themselves.METHODS: The mitochondrial biogenesis of CD26 and CD19 CAR-T cells during expansion was evaluated by the mitochondrial content, mitochondrial DNA copy numbers and genes involved in mitochondrial regulation. The metabolic profiling was investigated by the ATP production, mitochondrial quality and the expression of metabolism-related genes. Furthermore, we assessed the phenotypes of CAR-T cells through memory-related markers.
    RESULTS: We reported that CD26 CAR-T cells had elevated mitochondrial biogenesis, ATP production and oxidative phosphorylation at early expansion stage. However, the mitochondrial biogenesis, mitochondrial quality, oxidative phosphorylation and glycolytic activity were all weakened at later expansion stage. On the contrary, CD19 CAR-T cells did not exhibit such characteristics.
    CONCLUSION: CD26 CAR-T cells showed distinctive metabolic profiling during expansion that was extremely unfavorable to cell persistence and function. These findings may provide new insights for the optimization of CD26 CAR-T cells in terms of metabolism.
    Keywords:  CD19 CAR-T cells; CD26 CAR-T cells; glycolysis; metabolism; mitochondrial biogenesis
    DOI:  https://doi.org/10.1080/08923973.2023.2231632
  7. Ageing Res Rev. 2023 Jun 26. pii: S1568-1637(23)00152-6. [Epub ahead of print] 101993
    Immunometabolism and immune response regulate macrophage function in atherosclerosis.
    Sheng Xue, Zhe Su, Dacheng Liu.
      Macrophages are crucial in the progression of atherosclerotic cardiovascular disease (ASCVD). In the atherosclerotic lesions, macrophages play a central role in maintaining inflammatory response, promoting plaque development, and facilitating thrombosis. Increasing studies indicate that metabolic reprogramming and immune response mediate macrophage functional changes in all stages of atherosclerosis. In this review article, we explain how metabolic changes in glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, fatty acid synthesis, fatty acid oxidation, and cholesterol metabolism regulate macrophage function in atherosclerosis. We discuss how immune response to oxidized lipids regulate macrophage function in atherosclerosis. Additionally, we explore how abnormal metabolism leads to macrophage mitochondrial dysfunction in atherosclerosis.
    Keywords:  Atherosclerosis; Immune response; Immunometabolism; Macrophage; Oxidation-specific epitopes
    DOI:  https://doi.org/10.1016/j.arr.2023.101993
  8. Cell Metab. 2023 Jun 20. pii: S1550-4131(23)00213-9. [Epub ahead of print]
    Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy.
    Weiping Zou, Douglas R Green.
      Metabolic programming in the tumor microenvironment (TME) alters tumor immunity and immunotherapeutic response in tumor-bearing mice and patients with cancer. Here, we review immune-related functions of core metabolic pathways, key metabolites, and crucial nutrient transporters in the TME, discuss their metabolic, signaling, and epigenetic impact on tumor immunity and immunotherapy, and explore how these insights can be applied to the development of more effective modalities to potentiate the function of T cells and sensitize tumor cell receptivity to immune attack, thereby overcoming therapeutic resistance.
    Keywords:  T cell; checkpoint; immunotherapy; metabolism; metabolite; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2023.06.003
  9. Int Immunopharmacol. 2023 Jun 24. pii: S1567-5769(23)00869-X. [Epub ahead of print]121 110546
    The interplay between microbial metabolites and macrophages in cardiovascular diseases: A comprehensive review.
    Yongzheng Yang, Sajad Karampoor, Rasoul Mirzaei, Leonid Borozdkin, Ping Zhu.
      The gut microbiome has emerged as a crucial player in developing and progressing cardiovascular diseases (CVDs). Recent studies have highlighted the role of microbial metabolites in modulating immune cell function and their impact on CVD. Macrophages, which have a significant function in the pathogenesis of CVD, are very vulnerable to the effects of microbial metabolites. Microbial metabolites, such as short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), have been linked to atherosclerosis and the regulation of immune functions. Butyrate has been demonstrated to reduce monocyte migration and inhibit monocyte attachment to injured endothelial cells, potentially contributing to the attenuation of the inflammatory response and the progression of atherosclerosis. On the other hand, TMAO, another compound generated by gut bacteria, has been linked to atherosclerosis due to its impact on lipid metabolism and the accumulation of cholesterol in macrophages. Indole-3-propionic acid, a tryptophan metabolite produced solely by microbes, has been found to promote the development of atherosclerosis by stimulating macrophage reverse cholesterol transport (RCT) and raising the expression of ABCA1. This review comprehensively discusses how various microbiota-produced metabolites affect macrophage polarization, inflammation, and foam cell formation in CVD. We also highlight the mechanisms underlying these effects and the potential therapeutic applications of targeting microbial metabolites in treating CVD.
    Keywords:  CVD; Indole-3-propionic acid; Macrophage; Microbiota metabolites; SCFAs; TMAO
    DOI:  https://doi.org/10.1016/j.intimp.2023.110546
  10. Antioxidants (Basel). 2023 May 28. pii: 1166. [Epub ahead of print]12(6):
    Trehalose Inhibits Inflammatory Responses through Mitochondrial Reprogramming in RAW 264.7 Macrophages.
    Seungmin Yu, Hyejeong Park, Wooki Kim.
      Studies reported the beneficial effects of trehalose on metabolic syndromes, hyperlipidemia, and autophagy, but its action mechanisms are still poorly understood. Even though trehalose is digested by disaccharidase and absorbed in the intestine, intact molecules encounter immune cells which form a solid balance between the allowance of nutritive substances and the removal of harmful pathogens. In this regard, the polarization of intestinal macrophages into an anti-inflammatory phenotype through metabolic regulation is emerging as a therapeutic strategy for the prevention of gastrointestinal inflammation. The current study investigated the effects of trehalose on immunological phenotypes, energy metabolism, and LPS-induced macrophage mitochondrial functioning. Results indicate that trehalose reduces prostaglandin E2 and nitric oxide, which are inflammatory mediators of LPS-induced macrophages. In addition, trehalose further significantly suppressed inflammatory cytokines and mediators via energy metabolism reprogramming towards M2-like status in LPS-stimulated macrophages.
    Keywords:  anti-inflammatory; glycolysis; macrophage; metabolic reprogramming; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/antiox12061166
  11. Cell Immunol. 2023 Jun 20. pii: S0008-8749(23)00080-1. [Epub ahead of print]390 104741
    Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring.
    Anjali S Yennemadi, Gráinne Jameson, Mary Glass, Carolina De Pasquale, Joseph Keane, Massimiliano Bianchi, Gina Leisching.
      Although clinically effective, the actions of IFNα, either produced endogenously or by therapeutic delivery, remain poorly understood. Emblematic of this research gap is the disparate array of notable side effects that occur in susceptible individuals, such as neuropsychiatric consequences, autoimmune phenomena, and infectious complications. We hypothesised that these complications are driven at least in part by dysregulated cellular metabolism. Male Wistar rats were treated with either 170,000 IU/kg human recombinant IFNα-2a or BSA/saline (0.9% NaCl) three times per week for three weeks. Bone marrow (BM) immune cells were isolated from the excised femurs for glycolytic rate and mitochondrial function assessment using Agilent Seahorse Technology. Frequencies of immune cell populations were assessed by flow cytometry to determine whether leukopoietic changes had occurred in both blood and BM. Plasma levels of lactate and succinate were also determined. BMDMs were metabolically assessed as above, as well as their metabolic response to an antigenic stimulus (iH37Rv). We observed that BM immune cells from IFN-treated rats exhibit a hypermetabolic state (increased basal OCR/GlycoPER) with decreased mitochondrial metabolic respiration and increased non-mitochondrial OCR. Flow cytometry results indicated an increase in immature granulocytes (RP1- SSChi CD45lo) only in the blood, together with increased succinate levels in the plasma. BMDMs from IFN-treated rats retained the hypermetabolic phenotype after differentiation and failed to induce a step-up in glycolysis and mitochondrial respiration after bacterial stimulation. This work provides the first evidence of the effects of IFNα treatment in inducing hypermetabolic immune features that are associated with markers of inflammation, leukopoiesis, and defective responses to bacterial stimulation.
    Keywords:  Glycolysis; Interferon alpha; Interferon therapy; Macrophages; Metabolism; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.cellimm.2023.104741
  12. Immunohorizons. 2023 Jun 01. 7(6): 493-507
    Serendipitous Discovery of T Cell-Produced KLK1b22 as a Regulator of Systemic Metabolism.
    Matthew L Arwood, Im-Hong Sun, Chirag H Patel, Im-Meng Sun, Min-Hee Oh, Ian A Bettencourt, Michael D Claiborne, Yee Chan-Li, Liang Zhao, Adam T Waickman, Orestes Mavrothalassitis, Jiayu Wen, Susan Aja, Jonathan D Powell.
      In order to study mechanistic/mammalian target of rapamycin's role in T cell differentiation, we generated mice in which Rheb is selectively deleted in T cells (T-Rheb-/- C57BL/6J background). During these studies, we noted that T-Rheb-/- mice were consistently heavier but had improved glucose tolerance and insulin sensitivity as well as a marked increase in beige fat. Microarray analysis of Rheb-/- T cells revealed a marked increase in expression of kallikrein 1-related peptidase b22 (Klk1b22). Overexpression of KLK1b22 in vitro enhanced insulin receptor signaling, and systemic overexpression of KLK1b22 in C57BL/6J mice also enhances glucose tolerance. Although KLK1B22 expression was markedly elevated in the T-Rheb-/- T cells, we never observed any expression in wild-type T cells. Interestingly, in querying the mouse Immunologic Genome Project, we found that Klk1b22 expression was also increased in wild-type 129S1/SVLMJ and C3HEJ mice. Indeed, both strains of mice demonstrate exceptionally improved glucose tolerance. This prompted us to employ CRISPR-mediated knockout of KLK1b22 in 129S1/SVLMJ mice, which in fact led to reduced glucose tolerance. Overall, our studies reveal (to our knowledge) a novel role for KLK1b22 in regulating systemic metabolism and demonstrate the ability of T cell-derived KLK1b22 to regulate systemic metabolism. Notably, however, further studies have revealed that this is a serendipitous finding unrelated to Rheb.
    DOI:  https://doi.org/10.4049/immunohorizons.2300016
  13. Int Immunopharmacol. 2023 Jun 22. pii: S1567-5769(23)00855-X. [Epub ahead of print]121 110532
    IL-27 enhances peripheral B cell glycolysis of rheumatoid arthritis patients via activating mTOR signaling.
    Jingjing Qi, Jiaqing Liu, Xiangge Zhao, Huina Huang, Yawei Tang, Xia Li.
      Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 on B cell metabolism and clarify the mechanisms via which IL-27 enhancing glycolysis to induce B cells hyperactivation. Peripheral CD19+ B cells were purified from healthy controls (HC) and RA patients and then cultured with or without anti-CD40/CpG and glycolysis inhibitor 2-deoxy-D-glucose (2-DG) or mTOR inhibitor rapamycin. Furthermore, the isolated CD19+ B cells were treated by HC serum or RA serum in the presence and absence of recombinant human IL-27 or anti-IL-27 neutralizing antibodies or 2-DG or rapamycin. The B cell glycolysis level, proliferation, differentiation and inflammatory actions were detected by qPCR, flow cytometry or ELISA. We found that the glycolysis in RA B cells was increased significantly compared with HC B cells. Glycolysis inhibition downregulated the proliferation, differentiation, and inflammatory actions of RA B cells. RA serum and IL-27 promoted B cell glycolysis, which could be obviously rescued by anti-IL-27 antibodies or mTOR inhibitor rapamycin. Our results suggest that the enhanced cellular glycolysis of RA B cells induced by IL-27 may contribute to B cells hyperactivation through activating the mTOR signaling pathway.
    Keywords:  B cells Glycolysis Rheumatoid arthritis Interleukin-27
    DOI:  https://doi.org/10.1016/j.intimp.2023.110532
  14. J Transl Med. 2023 Jun 30. 21(1): 427
    Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviates atherosclerosis through the modulation of M1 polarization.
    Ze-da-Zhong Su, Chun-Qiu Li, Hua-Wei Wang, Min-Ming Zheng, Qing-Wei Chen.
      BACKGROUND: Inflammation and immune dysfunction with classically activated macrophages(M1) infiltration are important mechanisms in the progression of atherosclerosis (AS). Dynamin-related protein 1 (DRP1)-dependent mitochondrial fission is a novel target for alleviating inflammatory diseases. This study aimed to investigate the effects of DRP1 inhibitor Mdivi-1 on AS.METHODS: ApoE-/- mice were fed with a high-fat diet supplemented with or without Mdivi-1. RAW264.7 cells were stimulated by ox-LDL, pretreated with or without MCC950, Mito-TEMPO, or Mdivi-1. The burden of plaques and foam cell formation were determined using ORO staining. The blood lipid profles and inflammatory cytokines in serum were detected by commercial kits and ELISA, respectively. The mRNA expression of macrophage polarization markers, activation of NLRP3 and the phosphorylation state of DRP1 were detected. Mitochondrial reactive oxygen species (mito-ROS), mitochondrial staining, ATP level and mitochondrial membrane potential were detected by mito-SOX, MitoTracker, ATP determination kit and JC-1 staining, respectively.
    RESULTS: In vivo, Mdivi-1 reduced the plaque areas, M1 polarization, NLRP3 activation and DRP1 phosphorylation at Ser616. In vitro, oxidized low-density lipoprotein (ox-LDL) triggered M1 polarization, NLRP3 activation and abnormal accumulation of mito-ROS. MCC950 and Mito-TEMPO suppressed M1 polarization mediated foam cell formation. Mito-TEMPO significantly inhibited NLRP3 activation. In addition, Mdivi-1 reduced foam cells by inhibiting M1 polarization. The possible mechanisms responsible for the anti-atherosclerotic effects of Mdivi-1 on reducing M1 polarization were associated with suppressing mito-ROS/NLRP3 pathway by inhibiting DRP1 mediated mitochondrial fission. In vitro, similar results were observed by DRP1 knockdown.
    CONCLUSION: Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviated atherogenesis via suppressing mito-ROS/NLRP3-mediated M1 polarization, indicating DRP1-dependent mitochondrial fission as a potential therapeutic target for AS.
    Keywords:  Atherosclerosis; DRP1; M1 polarization; Mdivi-1; Mitochondrial fission; NLRP3 inflammasome
    DOI:  https://doi.org/10.1186/s12967-023-04270-9
  15. Cell Biol Int. 2023 Jun 27.
    LACC1: A critical involvement in macrophage immunometabolism.
    Yaling Li, Zhixiong Wu, Xiaoli Tan, Liang Tang, Fan Ouyang.
      Laccase domain-containing 1 (LACC1) protein is an enzyme highly expressed in inflammatory macrophages, and studies have shown that it has a key role in diseases such as inflammatory bowel disease, arthritis, and microbial infections. Therefore, in this review, we focus on LACC1-mediated catalysis. In detail, LACC1 converts l-CITrulline (l-CIT) to l-ORNithine (l-ORN) and isocyanic acid in mice and humans and acts as a bridge between proinflammatory nitric oxide synthase (NOS2) and polyamine immunometabolism, thus exerting anti-inflammatory and antibacterial effects. Considering the actions of LACC1, targeting LACC1 may be a potent therapeutic avenue for inflammation-related diseases and microbial infection diseases.
    Keywords:  LACC1; critical; immunometabolism; involvement; macrophage
    DOI:  https://doi.org/10.1002/cbin.12063
  16. Front Pharmacol. 2023 ;14 1161810
    Propofol inhibits neuroinflammation and metabolic reprogramming in microglia in vitro and in vivo.
    Shuyuan Guan, Lingbin Sun, Xihua Wang, Xirui Huang, Tao Luo.
      Microglial activation-induced neuroinflammation is closely related to the development of sepsis-associated encephalopathy. Accumulating evidence suggests that changes in the metabolic profile of microglia is crucial for their response to inflammation. Propofol is widely used for sedation in mechanically ventilated patients with sepsis. Here, we investigate the effect of propofol on lipopolysaccharide-induced neuroinflammation, neuronal injuries, microglia metabolic reprogramming as well as the underlying molecular mechanisms. The neuroprotective effects of propofol (80 mg/kg) in vivo were measured in the lipopolysaccharide (2 mg/kg)-induced sepsis in mice through behavioral tests, Western blot analysis and immunofluorescent staining. The anti-inflammatory effects of propofol (50 μM) in microglial cell cultures under lipopolysaccharide (10 ng/ml) challenge were examined with Seahorse XF Glycolysis Stress test, ROS assay, Western blot, and immunofluorescent staining. We showed that propofol treatment reduced microglia activation and neuroinflammation, inhibited neuronal apoptosis and improved lipopolysaccharide-induced cognitive dysfunction. Propofol also attenuated lipopolysaccharide-stimulated increases of inducible nitric oxide synthase, nitric oxide, tumor necrosis factor-α, interlukin-1β and COX-2 in cultured BV-2 cells. Propofol-treated microglia showed a remarkable suppression of lipopolysaccharide-induced HIF-1α, PFKFB3, HK2 expression and along with downregulation of the ROS/PI3K/Akt/mTOR signaling pathway. Moreover, propofol attenuated the enhancement of mitochondrial respiration and glycolysis induced by lipopolysaccharide. Together, our data suggest that propofol attenuated inflammatory response by inhibiting metabolic reprogramming, at least in part, through downregulation of the ROS/PI3K/Akt/mTOR/HIF-1α signaling pathway.
    Keywords:  HIF-1α; Microglia; Propofol; metabolic reprogramming; neuroinflammation
    DOI:  https://doi.org/10.3389/fphar.2023.1161810
  17. Nat Genet. 2023 Jun 29.
    Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.
    Caleb A Lareau, Sonia M Dubois, Frank A Buquicchio, Yu-Hsin Hsieh, Kopal Garg, Pauline Kautz, Lena Nitsch, Samantha D Praktiknjo, Patrick Maschmeyer, Jeffrey M Verboon, Jacob C Gutierrez, Yajie Yin, Evgenij Fiskin, Wendy Luo, Eleni P Mimitou, Christoph Muus, Rhea Malhotra, Sumit Parikh, Mark D Fleming, Lena Oevermann, Johannes Schulte, Cornelia Eckert, Anshul Kundaje, Peter Smibert, Santosha A Vardhana, Ansuman T Satpathy, Aviv Regev, Vijay G Sankaran, Suneet Agarwal, Leif S Ludwig.
      Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.
    DOI:  https://doi.org/10.1038/s41588-023-01433-8
  18. Front Immunol. 2023 ;14 1121864
    Hypoxia-altered cholesterol homeostasis enhances the expression of interferon-stimulated genes upon SARS-CoV-2 infections in monocytes.
    Rebekka Bauer, Sofie Patrizia Meyer, Rebecca Raue, Megan A Palmer, Vanesa Maria Guerrero Ruiz, Giulia Cardamone, Silvia Rösser, Milou Heffels, Fabian Roesmann, Alexander Wilhelm, Dieter Lütjohann, Kathi Zarnack, Dominik Christian Fuhrmann, Marek Widera, Tobias Schmid, Bernhard Brüne.
      Hypoxia contributes to numerous pathophysiological conditions including inflammation-associated diseases. We characterized the impact of hypoxia on the immunometabolic cross-talk between cholesterol and interferon (IFN) responses. Specifically, hypoxia reduced cholesterol biosynthesis flux and provoked a compensatory activation of sterol regulatory element-binding protein 2 (SREBP2) in monocytes. Concomitantly, a broad range of interferon-stimulated genes (ISGs) increased under hypoxia in the absence of an inflammatory stimulus. While changes in cholesterol biosynthesis intermediates and SREBP2 activity did not contribute to hypoxic ISG induction, intracellular cholesterol distribution appeared critical to enhance hypoxic expression of chemokine ISGs. Importantly, hypoxia further boosted chemokine ISG expression in monocytes upon infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Mechanistically, hypoxia sensitized toll-like receptor 4 (TLR4) signaling to activation by SARS-CoV-2 spike protein, which emerged as a major signaling hub to enhance chemokine ISG induction following SARS-CoV-2 infection of hypoxic monocytes. These data depict a hypoxia-regulated immunometabolic mechanism with implications for the development of systemic inflammatory responses in severe cases of coronavirus disease-2019 (COVID-19).
    Keywords:  COVID-19; SREBP2; cholesterol; hypoxia; immunometabolism; systemic inflammation
    DOI:  https://doi.org/10.3389/fimmu.2023.1121864
  19. Exerc Immunol Rev. 2023 ;29 54-87
    A Scoping Review on the Effects of Physical Exercise and Fitness on Peripheral Leukocyte Energy Metabolism in Humans.
    Charles F Hodgman, Rebekah M Hunt, Justin C Crane, Mahmoud T Elzayat, Emily C LaVoy.
      Background: Both acute and chronic exercise have profound effects on systemic metabolism and the immune system. While acute exercise transiently disturbs energy homeostasis and elicits acute inflammation, exercise training improves systemic metabolic capacity, lowers basal inflammation, and reduces infection risk. Accordingly, accumulating evidence indicates links between systemic and immune cell metabolism and suggests that cellular metabolism may be an important way exercise influences immune function. Yet, no reviews have systematically surveyed the literature in this area.Aims: The aims of this scoping review were to collect, summarize, and provide descriptive analysis of literature on the effects of acute exercise, chronic exercise, and physical fitness on peripheral leukocyte energy metabolism of human adults.
    Methods: Reports were retrieved from the databases Pubmed, Scopus, and Embase and hierarchically filtered for eligibility. Eligible reports were those that implemented acute or chronic exercise interventions, or assessed physical fitness, in relation to the regulation or function of leukocyte energy metabolism in human adults. Data were charted from eligible reports by two independent reviewers, confirmed by conference, and organized for reporting.
    Results & Conclusion: Results suggest acute exercise can influence the regulation and function of leukocyte metabolism, with some similarities to what has been previously documented in skeletal muscle. Data also evidence that exercise training and/ or physical fitness alters cellular metabolic regulation and function. Improvements in markers of cell respiratory function or mitochondrial regulation were frequently observed following training or with greater fitness. However, notable gaps in the literature remain. These gaps include: the effects of acute exercise and exercise training on leukocyte glycolysis, the effects of resistance and concurrent exercise, and potential differences in the effects of exercise between immune cell types and subsets. Future research is encouraged to fill the latter gaps and further delineate how exercise influences the immune system and can be used to support overall health.
    Keywords:  Exercise; Human; Leukocyte; Metabolism; Physical Fitness
  20. Mucosal Immunol. 2023 Jun 27. pii: S1933-0219(23)00051-X. [Epub ahead of print]
    Metabolic Adaption of Mucosal Macrophages: Is Metabolism a Driver of Persistence Across Tissues?
    Clare L Bennett, Georgia Perona-Wright.
      Macrophages play essential roles in tissue homeostasis, defence, and repair. Their functions are highly tissue-specific and, when damage and inflammation stimulate repopulation by circulating monocytes, the incoming monocytes rapidly acquire the same, tissue-specific functions as the previous, resident macrophages. Several environmental factors are thought to guide the functional differentiation of recruited monocytes, including metabolic pressures imposed by the fuel sources available in each tissue. Here we discuss whether such a model of metabolic determinism can be applied to macrophage differentiation across barrier sites, from the lung to the skin. We suggest an alternative model, in which metabolic phenotype is a consequence of macrophage longevity rather than an early driver of tissue-specific adaption.
    DOI:  https://doi.org/10.1016/j.mucimm.2023.06.006
  21. J Transl Med. 2023 Jun 28. 21(1): 419
    Intrahepatic macrophage reprogramming associated with lipid metabolism in hepatitis B virus-related acute-on-chronic liver failure.
    Bo Peng, Hao Li, Kai Liu, Pengpeng Zhang, Quan Zhuang, Junhui Li, Min Yang, Ke Cheng, Yingzi Ming.
      BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe syndrome with high short-term mortality, but the pathophysiology still remains largely unknown. Immune dysregulation and metabolic disorders contribute to the progression of ACLF, but the crosstalk between immunity and metabolism during ACLF is less understood. This study aims to depict the immune microenvironment in the liver during ACLF, and explore the role of lipid metabolic disorder on immunity.METHODS: Single-cell RNA-sequencing (scRNA-seq) was performed using the liver non-parenchymal cells (NPCs) and peripheral blood mononuclear cells (PBMCs) from healthy controls, cirrhosis patients and ACLF patients. A series of inflammation-related cytokines and chemokines were detected using liver and plasma samples. The lipid metabolomics targeted free fatty acids (FFAs) in the liver was also detected.
    RESULTS: The scRNA-seq analysis of liver NPCs showed a significant increase of monocytes/macrophages (Mono/Mac) infiltration in ACLF livers, whereas the resident Kupffer cells (KCs) were exhausted. A characterized TREM2+ Mono/Mac subpopulation was identified in ACLF, and showed immunosuppressive function. Combined with the scRNA-seq data from PBMCs, the pseudotime analysis revealed that the TREM2+ Mono/Mac were differentiated from the peripheral monocytes and correlated with lipid metabolism-related genes including APOE, APOC1, FABP5 and TREM2. The targeted lipid metabolomics proved the accumulation of unsaturated FFAs associated with α-linolenic acid (α-LA) and α-LA metabolism and beta oxidation of very long chain fatty acids in the ACLF livers, indicating that unsaturated FFAs might promote the differentiation of TREM2+ Mono/Mac during ACLF.
    CONCLUSIONS: The reprogramming of macrophages was found in the liver during ACLF. The immunosuppressive TREM2+ macrophages were enriched in the ACLF liver and contributed to the immunosuppressive hepatic microenvironment. The accumulation of unsaturated FFAs in the ACLF liver promoted the reprogramming of the macrophages. It might be a potential target to improve the immune deficiency of ACLF patients through regulating lipid metabolism.
    Keywords:  Acute-on-chronic liver failure; Cirrhosis-associated immune dysfunction; Free fatty acids; Hepatitis B virus; Lipid metabolomics; TREM2; scRNA-seq
    DOI:  https://doi.org/10.1186/s12967-023-04294-1
  22. Redox Biol. 2023 Jun 16. pii: S2213-2317(23)00172-6. [Epub ahead of print]64 102771
    Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.
    Keman Xu, Fatma Saaoud, Ying Shao, Yifan Lu, Sheng Wu, Huaqing Zhao, Kaifu Chen, Roberto Vazquez-Padron, Xiaohua Jiang, Hong Wang, Xiaofeng Yang.
      To identify metabolomic reprogramming in early hyperlipidemia, unbiased metabolome was screened in four tissues from ApoE-/- mice fed with high fat diet (HFD) for 3 weeks. 30, 122, 67, and 97 metabolites in the aorta, heart, liver, and plasma, respectively, were upregulated. 9 upregulated metabolites were uremic toxins, and 13 metabolites, including palmitate, promoted a trained immunity with increased syntheses of acetyl-CoA and cholesterol, increased S-adenosylhomocysteine (SAH) and hypomethylation and decreased glycolysis. The cross-omics analysis found upregulation of 11 metabolite synthetases in ApoE‾/‾ aorta, which promote ROS, cholesterol biosynthesis, and inflammation. Statistical correlation of 12 upregulated metabolites with 37 gene upregulations in ApoE‾/‾ aorta indicated 9 upregulated new metabolites to be proatherogenic. Antioxidant transcription factor NRF2-/- transcriptome analysis indicated that NRF2 suppresses trained immunity-metabolomic reprogramming. Our results have provided novel insights on metabolomic reprogramming in multiple tissues in early hyperlipidemia oriented toward three co-existed new types of trained immunity.
    Keywords:  Early atherosclerosis; Metabolomes; Proinflammatory and anti-inflammatory metabolites; Trained immunity; Transcriptome
    DOI:  https://doi.org/10.1016/j.redox.2023.102771
  23. Cardiovasc Ther. 2023 ;2023 8774971
    The Regulation Network of Glycerolipid Metabolism as Coregulators of Immunotherapy-Related Myocarditis.
    Xiguang Yang, Xiaopeng Duan, Zhenglin Xia, Rui Huang, Ke He, Guoan Xiang.
      Background: To date, immunotherapy for patients with malignant tumors has shown a significant association with myocarditis. However, the mechanism of metabolic reprogramming changes for immunotherapy-related cardiotoxicity is still not well understood.Methods: The CD45+ single-cell RNA sequencing (scRNA-seq) of the Pdcd1-/-Ctla4+/- and wild-type mouse heart in GSE213486 was downloaded to demonstrate the heterogeneity of immunocyte atlas in immunotherapy-related myocarditis. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) spectrum metabolomics analysis detects the metabolic network differences. The drug prediction, organelle level interaction, mitochondrial level regulatory network, and phosphorylation site prediction for key regulators have also been screened via multibioinformatics analysis methods.
    Results: The scRNA analysis shows that the T cell is the main regulatory cell subpopulation in the pathological progress of immunotherapy-related myocarditis. Mitochondrial regulation pathway significantly participated in pseudotime trajectory- (PTT-) related differential expressed genes (DEGs) in the T cell subpopulation. Additionally, both the gene set enrichment analysis (GSEA) of PTT-related DEGs and LC-MS/MS metabolomics analysis showed that mitochondrial-regulated glycerolipid metabolism plays a central role in metabolic reprogramming changes for immunotherapy-related cardiotoxicity. Finally, the hub-regulated protease of diacylglycerol kinase zeta (Dgkz) was significantly identified and widely played various roles in glycerolipid metabolism, oxidative phosphorylation, and lipid kinase activation.
    Conclusion: Mitochondrial-regulated glycerolipid metabolism, especially the DGKZ protein, plays a key role in the metabolic reprogramming of immunotherapy-related myocarditis.
    DOI:  https://doi.org/10.1155/2023/8774971
  24. Front Immunol. 2023 ;14 1206733
    Oxylipin secretion by human CD3+ T lymphocytes in vitro is modified by the exogenous essential fatty acid ratio and life stage.
    Johanna von Gerichten, Annette L West, Nicola A Irvine, Elizabeth A Miles, Philip C Calder, Karen A Lillycrop, Graham C Burdge, Barbara A Fielding.
      Immune function changes across the life stages; for example, senior adults exhibit a tendency towards a weaker cell-mediated immune response and a stronger inflammatory response than younger adults. This might be partly mediated by changes in oxylipin synthesis across the life course. Oxylipins are oxidation products of polyunsaturated fatty acids (PUFAs) that modulate immune function and inflammation. A number of PUFAs are precursors to oxylipins, including the essential fatty acids (EFAs) linoleic acid (LA) and α-linolenic acid (ALA). LA and ALA are also substrates for synthesis of longer chain PUFAs. Studies with stable isotopes have shown that the relative amounts of LA and ALA can influence their partitioning by T lymphocytes between conversion to longer chain PUFAs and to oxylipins. It is not known whether the relative availability of EFA substrates influences the overall pattern of oxylipin secretion by human T cells or if this changes across the life stages. To address this, the oxylipin profile was determined in supernatants from resting and mitogen activated human CD3+ T cell cultures incubated in medium containing an EFA ratio of either 5:1 or 8:1 (LA : ALA). Furthermore, oxylipin profiles in supernatants of T cells from three life stages, namely fetal (derived from umbilical cord blood), adults and seniors, treated with the 5:1 EFA ratio were determined. The extracellular oxylipin profiles were affected more by the EFA ratio than mitogen stimulation such that n-3 PUFA-derived oxylipin concentrations were higher with the 5:1 EFA ratio than the 8:1 ratio, possibly due to PUFA precursor competition for lipoxygenases. 47 oxylipin species were measured in all cell culture supernatants. Extracellular oxylipin concentrations were generally higher for fetal T cells than for T cells from adult and senior donors, although the composition of oxylipins was similar across the life stages. The contribution of oxylipins towards an immunological phenotype might be due to the capacity of T cells to synthesize oxylipins rather than the nature of the oxylipins produced.
    Keywords:  T lymphocytes; eicosanoid; immunosenescence; lipid metabolism; oxylipin
    DOI:  https://doi.org/10.3389/fimmu.2023.1206733
  25. Virology. 2023 Jun 21. pii: S0042-6822(23)00134-4. [Epub ahead of print]585 196-204
    Niclosamide inhibits Newcastle disease virus replication in chickens by perturbing the cellular glycolysis.
    Yoya Vashi, Ganesh Nehru, Sachin Kumar.
      Newcastle disease virus (NDV), a member of Paramyxoviridae family, is one of the most important pathogens in poultry. To ensure optimal environments for their replication and spread, viruses rely largely on host cellular metabolism. In the present study, we evaluated the small drug molecule niclosamide for its anti-NDV activity. Our study has shown that a sublethal dose of 1 μM niclosamide could drastically reduce NDV replication. The results showed that niclosamide has antiviral activity against NDV infection during in vitro, in ovo and in vivo assays. Pharmacologically inhibiting the glycolytic pathway remarkably reduced NDV RNA synthesis and infectious virion production. Our results suggest that the effect of niclosamide on cellular glycolysis could be the possible reason for the specific anti-NDV effect. This study could help us understand antiviral strategies against similar pathogens and may lead to novel therapeutic approaches through targeted inhibition of specific cellular metabolic pathways.
    Keywords:  Anti-viral; Glycolysis; Newcastle disease virus; Niclosamide
    DOI:  https://doi.org/10.1016/j.virol.2023.06.010
  26. Arthritis Rheumatol. 2023 Jun 30.
    Metabolomics and Machine Learning Identify Metabolic Differences and Potential Biomarkers for Frequent versus Infrequent Gout Flares.
    Ming Wang, Rui Li, Han Qi, Lei Pang, Lingling Cui, Zhen Liu, Jie Lu, Rong Wang, Shuhui Hu, Ningning Liang, Yongzhen Tao, Nicola Dalbeth, Tony R Merriman, Robert Terkeltaub, Huiyong Yin, Changgui Li.
      OBJECTIVES: To discover differential metabolites and pathways underlying infrequent gout flares (InGF) and frequent gout flares (FrGF) using metabolomics and establish a predictive model by machine learning (ML) algorithms.METHODS: Serum samples from a discovery cohort with 163 InGF and 239 FrGF patients were analyzed by mass spectrometry-based untargeted metabolomics to profile differential metabolites and explore dysregulated metabolic pathways using pathway enrichment analysis and network propagation-based algorithms. ML algorithms were performed to establish a predictive model based on selected metabolites, which was further optimized by a quantitative targeted metabolomics method and validated in an independent validation cohort with 97 participants with InGF and 139 participants with FrGF.
    RESULTS: 439 differential metabolites between InGF and FrGF groups were identified. Top dysregulated pathways included carbohydrates, amino acids, bile acids, and nucleotide metabolism. Subnetworks with maximum disturbances in the global metabolic networks featured cross-talk between purine metabolism and caffeine metabolism, as well as interactions among pathways involving primary bile acid biosynthesis, taurine and hypotaurine metabolism, alanine, aspartate and glutamate metabolism, suggesting epigenetic modifications and gut microbiome in metabolic alterations underlying InGF and FrGF. Potential metabolite biomarkers were identified using ML-based multivariable selection and further validated by targeted metabolomics. Area under receiver operating characteristics curve for differentiating InGF and FrGF achieved 0.88 and 0.67 for the discovery and validation cohorts, respectively.
    CONCLUSIONS: Systematic metabolic alterations underlie InGF and FrGF, and distinct profiles are associated with differences in gout flare frequencies. Predictive modeling based on selected metabolites from metabolomics can differentiate InGF and FrGF.
    DOI:  https://doi.org/10.1002/art.42635
  27. Front Immunol. 2023 ;14 1128700
    Apilimod activates the NLRP3 inflammasome through lysosome-mediated mitochondrial damage.
    Yingting Hou, Hongbin He, Ming Ma, Rongbin Zhou.
      NLRP3 is an important innate immune sensor that responses to various signals and forms the inflammasome complex, leading to IL-1β secretion and pyroptosis. Lysosomal damage has been implicated in NLRP3 inflammasome activation in response to crystals or particulates, but the mechanism remains unclear. We developed the small molecule library screening and found that apilimod, a lysosomal disruptor, is a selective and potent NLRP3 agonist. Apilimod promotes the NLRP3 inflammasome activation, IL-1β secretion, and pyroptosis. Mechanismically, while the activation of NLRP3 by apilimod is independent of potassium efflux and directly binding, apilimod triggers mitochondrial damage and lysosomal dysfunction. Furthermore, we found that apilimod induces TRPML1-dependent calcium flux in lysosomes, leading to mitochondrial damage and the NLRP3 inflammasome activation. Thus, our results revealed the pro-inflammasome activity of apilimod and the mechanism of calcium-dependent lysosome-mediated NLRP3 inflammasome activation.
    Keywords:  NLRP3 inflammasome; activation; apilimod; lysosome; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2023.1128700
  28. EMBO Mol Med. 2023 Jun 26. e16845
    Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation.
    Enchen Zhou, Xiaoke Ge, Hiroyuki Nakashima, Rumei Li, Hendrik J P van der Zande, Cong Liu, Zhuang Li, Christoph Müller, Franz Bracher, Yassene Mohammed, Jan Freark de Boer, Folkert Kuipers, Bruno Guigas, Christopher K Glass, Patrick C N Rensen, Martin Giera, Yanan Wang.
      Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3-Leiden. CETP mice, a well-established translational model that develops diet-induced human-like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet-induced hepatic steatosis and inflammation in a strictly LXRα-dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.
    Keywords:  Kupffer cell; desmosterol; liver X receptor; nonalcoholic steatohepatitis; Δ24-dehydrocholesterol reductase
    DOI:  https://doi.org/10.15252/emmm.202216845
  29. Exerc Immunol Rev. 2023 ;29 111-120
    The anti-inflammatory and bioregulatory effects of habitual exercise in high-fat diet-induced obesity involve crown-like structures and MCP-1 in white adipose tissue.
    Isabel Gálvez, María Dolores Hinchado, Leticia Martín-Cordero, Francisco Javier Morán-Plata, Gerry Graham, Javier Francisco-Morcillo, Eduardo Ortega.
      Macrophage accumulation in the adipose tissue and changes in their inflammatory phenotype is a hallmark of obesity-induced inflammation, notably forming inflammatory structures known as "crown-like structures (CLS)". Exercise can be a key strategy to improve inflammation-related complications, but it is crucial to consider that, although exercise generally exerts systemic and local anti-inflammatory effects, this depends on the basal inflammatory status and exercise modality. In this context, the "bioregulatory effect of exercise" implies to achieve the reduction or prevention of an excessive inflammatory response and also the preservation or stimulation of the innate response. In the present work, our aim was to evaluate the effect of regular exercise on adipose tissue inflammation in high-fat diet-induced obesity in mice, as reflected by macrophage infiltration and phenotype, and CLS formation, together with a potential role for the chemokine MCP-1 in this process. Results showed that obesity is associated with greater MCP-1 expression (p<0.05), macrophage accumulation (p<0.05), and CLS presence (p<0.001). Regular exercise reduced macrophage accumulation (p<0.05), MCP-1 expression (p<0.01), and CLS presence (p<0.05) in obese mice; while it increased macrophage and CLS presence (p<0.01), MCP-1 expression (p<0.05), and M2 polarization (p<0.05) in lean mice. MCP-1 was associated with the proliferation of CLS, showing the first image demonstrating a potential role of this chemokine in the development of these structures. Altogether, these results confirm, for the first time, the "bioregulatory effect of exercise" in the adipose tissue: reducing inflammation in individuals with an elevated inflammatory setpoint, but stimulating this response of the immune system in healthy individuals.
    Keywords:  CCL2; CLS; Inflammation; Macrophages; Phenotype
  30. Biomolecules. 2023 06 15. pii: 993. [Epub ahead of print]13(6):
    Inhibition of the Mitochondrial Carnitine/Acylcarnitine Carrier by Itaconate through Irreversible Binding to Cysteine 136: Possible Pathophysiological Implications.
    Nicola Giangregorio, Annamaria Tonazzi, Lara Console, Mariafrancesca Scalise, Cesare Indiveri.
      BACKGROUND: The carnitine/acylcarnitine carrier (CAC) represents the route of delivering acyl moieties to the mitochondrial matrix for accomplishing the fatty acid β-oxidation. The CAC has a couple of Cys residues (C136 and C155) most reactive toward ROS and redox signaling compounds such as GSH, NO, and H2S. Among physiological compounds reacting with Cys, itaconate is produced during inflammation and represents the connection between oxidative metabolism and immune responses. The possible interaction between the CAC and itaconate has been investigated.METHODS: the modulatory effects of itaconate on the transport activity of the native and recombinant CAC were tested using the proteoliposome experimental model together with site-directed mutagenesis and computational analysis.
    RESULTS: Itaconate reacts with the CAC causing irreversible inhibition. Dose-response experiment performed with the native and recombinant protein showed IC50 for itaconate of 11 ± 4.6 mM and 8.4 ± 2.9 mM, respectively. The IC50 decreased to 3.8 ± 1.0 mM by lowering the pH from pH 7.0 to pH 6.5. Inhibition kinetics revealed a non-competitive type of inhibition. C136 is the main target of itaconate, as demonstrated by the increased IC50 of mutants in which this Cys was substituted by Val. The central role of C136 was confirmed by covalent docking. Administration of dimethyl itaconate to HeLa cells inhibited the CAC transport activity, suggesting that itaconate could react with the CAC also in intact cells.
    Keywords:  ROS; SLC25A20; carnitine; carrier; cysteines; itaconate; mitochondria
    DOI:  https://doi.org/10.3390/biom13060993
  31. Mol Immunol. 2023 Jun 26. pii: S0161-5890(23)00127-X. [Epub ahead of print]160 55-66
    S1P/S1PR1 axis promotes macrophage M1 polarization through NLRP3 inflammasome activation in Lupus nephritis.
    Jihua Tian, Sijia Chang, Jing Wang, Jingshu Chen, Huanyu Xu, Taiping Huang, Juanjuan Wang, Jing Kang, Weiping Fan, Yanhong Wang.
      Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) as well as the leading cause of mortality in patients. Previous studies revealed that S1P level is elevated in plasma samples of SLE patients and murine lupus models. FTY720, targeting S1P receptors, exhibited therapeutic effects in improving the nephritis symptoms of lupus mouse models. However, few studies have discussed the potential relevance of S1P/S1PR to the pathogenesis of LN. Macrophages have been shown to be an important causative agent of renal inflammation, while the pro-inflammatory M1-type promotes kidney injury and inflammation during LN. Importantly, macrophages express various S1P receptors, and how they respond to S1P in the setting of LN remains unclear. Therefore, we examined the level of S1P in the lupus MRL/lpr mice and explored the ensuing interaction of macrophages and S1P. We found that S1P level was elevated in the MRL/lpr mice with a subsequent enhancement of the S1PR1 expression, and blocking S1PR1 by FTY720, the nephritis symptoms of MRL/lpr mice were improved. Mechanistically, we demonstrated that elevated S1P level increase the M1-type macrophage accumulation. And the in-vitro studies proved that S1P/S1PR1 was involved in the promotion of macrophage polarization towards M1 type through activation of NLRP3 inflammasome. These findings confer a novel role to macrophage S1PR1 and provide a new perspective for targeting S1P during LN.
    Keywords:  Lupus nephritis; Macrophage polarization; NLR family pyrin domain-containing 3; Sphingosine-1-phosphate; Sphingosine-1-phosphate receptors
    DOI:  https://doi.org/10.1016/j.molimm.2023.06.006
  32. Int J Mol Sci. 2023 Jun 19. pii: 10351. [Epub ahead of print]24(12):
    Differential Lipidomics, Metabolomics and Immunological Analysis of Alcoholic and Non-Alcoholic Steatohepatitis in Mice.
    Erika Dorochow, Nico Kraus, Nicolas Chenaux-Repond, Sandra Pierre, Anja Kolbinger, Gerd Geisslinger, Cristina Ortiz, Christoph Welsch, Jonel Trebicka, Robert Gurke, Lisa Hahnefeld, Sabine Klein, Klaus Scholich.
      Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) are the leading causes of liver disease worldwide. To identify disease-specific pathomechanisms, we analyzed the lipidome, metabolome and immune cell recruitment in livers in both diseases. Mice harboring ASH or NASH had comparable disease severities regarding mortality rate, neurological behavior, expression of fibrosis marker and albumin levels. Lipid droplet size was higher in NASH than ASH and qualitative differences in the lipidome were mainly based on incorporation of diet-specific fatty acids into triglycerides, phosphatidylcholines and lysophosphatidylcholines. Metabolomic analysis showed downregulated nucleoside levels in both models. Here, the corresponding uremic metabolites were only upregulated in NASH suggesting stronger cellular senescence, which was supported by lower antioxidant levels in NASH as compared to ASH. While altered urea cycle metabolites suggest increased nitric oxide synthesis in both models, in ASH, this depended on increased L-homoarginine levels indicating a cardiovascular response mechanism. Interestingly, only in NASH were the levels of tryptophan and its anti-inflammatory metabolite kynurenine upregulated. Fittingly, high-content immunohistochemistry showed a decreased macrophage recruitment and an increased polarization towards M2-like macrophages in NASH. In conclusion, with comparable disease severity in both models, higher lipid storage, oxidative stress and tryptophan/kynurenine levels were seen in NASH, leading to distinct immune responses.
    Keywords:  alcoholic fatty liver disease; lipid droplets; lipidomics; metabolomics; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.3390/ijms241210351
  33. Sci Adv. 2023 Jun 30. 9(26): eadg3736
    Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy.
    Omar S Sarkar, Howard Donninger, Numan Al Rayyan, Lewis C Chew, Bryce Stamp, Xiang Zhang, Aaron Whitt, Chi Li, Melissa Hall, Robert A Mitchell, Alfred Zippelius, John Eaton, Jason A Chesney, Kavitha Yaddanapudi.
      Immune checkpoint inhibitor (ICI) therapy is effective against many cancers for a subset of patients; a large percentage of patients remain unresponsive to this therapy. One contributing factor to ICI resistance is accumulation of monocytic myeloid-derived suppressor cells (M-MDSCs), a subset of innate immune cells with potent immunosuppressive activity against T lymphocytes. Here, using lung, melanoma, and breast cancer mouse models, we show that CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function. Tumor-derived PGE2, a prostaglandin, directly induces CD73 expression in M-MDSCs via both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with T cell-suppressive activity, culminating in suppression of antitumor CD8+ T cell activity. Depletion of adenosine in the TME by the repurposed drug PEGylated adenosine deaminase (PEG-ADA) increases CD8+ T cell activity and enhances response to ICI therapy. Use of PEG-ADA can therefore be a therapeutic option to overcome resistance to ICIs in cancer patients.
    DOI:  https://doi.org/10.1126/sciadv.adg3736
  34. Int J Mol Sci. 2023 Jun 14. pii: 10113. [Epub ahead of print]24(12):
    The Effects of Mitochondrial Transplantation on Sepsis Depend on the Type of Cell from Which They Are Isolated.
    Yun-Seok Kim, Han A Reum Lee, Min Ji Lee, Ye Jin Park, Sehwan Mun, Chang June Yune, Tae Nyoung Chung, Jinkun Bae, Mi Jin Kim, Yong-Soo Choi, Kyuseok Kim.
      Previously, we have shown that mitochondrial transplantation in the sepsis model has immune modulatory effects. The mitochondrial function could have different characteristics dependent on cell types. Here, we investigated whether the effects of mitochondrial transplantation on the sepsis model could be different depending on the cell type, from which mitochondria were isolated. We isolated mitochondria from L6 muscle cells, clone 9 liver cells and mesenchymal stem cells (MSC). We tested the effects of mitochondrial transplantation using in vitro and in vivo sepsis models. We used the LPS stimulation of THP-1 cell, a monocyte cell line, as an in vitro model. First, we observed changes in mitochondrial function in the mitochondria-transplanted cells. Second, we compared the anti-inflammatory effects of mitochondrial transplantation. Third, we investigated the immune-enhancing effects using the endotoxin tolerance model. In the in vivo polymicrobial fecal slurry sepsis model, we examined the survival and biochemical effects of each type of mitochondrial transplantation. In the in vitro LPS model, mitochondrial transplantation with each cell type improved mitochondrial function, as measured by oxygen consumption. Among the three cell types, L6-mitochondrial transplantation significantly enhanced mitochondrial function. Mitochondrial transplantation with each cell type reduced hyper-inflammation in the acute phase of in vitro LPS model. It also enhanced immune function during the late immune suppression phase, as shown by endotoxin tolerance. These functions were not significantly different between the three cell types of origin for mitochondrial transplantation. However, only L6-mitochondrial transplantation significantly improved survival compared to the control in the polymicrobial intraabdominal sepsis model. The effects of mitochondria transplantation on both in vitro and in vivo sepsis models differed depending on the cell types of origin for mitochondria. L6-mitochondrial transplantation might be more beneficial in the sepsis model.
    Keywords:  hyperinflammation; immune modulation; immune paralysis; mitochondria dysfunction; mitochondria transplantation; sepsis
    DOI:  https://doi.org/10.3390/ijms241210113
  35. Nat Commun. 2023 Jun 30. 14(1): 3877
    Ultrasound-responsive low-dose doxorubicin liposomes trigger mitochondrial DNA release and activate cGAS-STING-mediated antitumour immunity.
    Chaoyu Wang, Ruoshi Zhang, Jia He, Lvshan Yu, Xinyan Li, Junxia Zhang, Sai Li, Conggang Zhang, Jonathan C Kagan, Jeffrey M Karp, Rui Kuai.
      DNA derived from chemotherapeutics-killed tumor cells is one of the most important damage-associated molecular patterns that can activate the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway in antigen-presenting cells (APCs) and promote antitumor immunity. However, conventional chemotherapy displays limited tumor cell killing and ineffective transfer of stable tumor DNA to APCs. Here we show that liposomes loaded with an optimized ratio of indocyanine green and doxorubicin, denoted as LID, efficiently generate reactive oxygen species upon exposure to ultrasound. LID plus ultrasound enhance the nuclear delivery of doxorubicin, induce tumor mitochondrial DNA oxidation, and promote oxidized tumor mitochondrial DNA transfer to APCs for effective activation of cGAS-STING signaling. Depleting tumor mitochondrial DNA or knocking out STING in APCs compromises the activation of APCs. Furthermore, systemic injection of LID plus ultrasound over the tumor lead to targeted cytotoxicity and STING activation, eliciting potent antitumor T cell immunity, which upon the combination with immune checkpoint blockade leads to regression of bilateral MC38, CT26, and orthotopic 4T1 tumors in female mice. Our study sheds light on the importance of oxidized tumor mitochondrial DNA in STING-mediated antitumor immunity and may inspire the development of more effective strategies for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-023-39607-x
  36. Microbiol Mol Biol Rev. 2023 Jun 26. e0019822
    How Bacterial Pathogens Coordinate Appetite with Virulence.
    Nick D Pokorzynski, Eduardo A Groisman.
      Cells adjust growth and metabolism to nutrient availability. Having access to a variety of carbon sources during infection of their animal hosts, facultative intracellular pathogens must efficiently prioritize carbon utilization. Here, we discuss how carbon source controls bacterial virulence, with an emphasis on Salmonella enterica serovar Typhimurium, which causes gastroenteritis in immunocompetent humans and a typhoid-like disease in mice, and propose that virulence factors can regulate carbon source prioritization by modifying cellular physiology. On the one hand, bacterial regulators of carbon metabolism control virulence programs, indicating that pathogenic traits appear in response to carbon source availability. On the other hand, signals controlling virulence regulators may impact carbon source utilization, suggesting that stimuli that bacterial pathogens experience within the host can directly impinge on carbon source prioritization. In addition, pathogen-triggered intestinal inflammation can disrupt the gut microbiota and thus the availability of carbon sources. By coordinating virulence factors with carbon utilization determinants, pathogens adopt metabolic pathways that may not be the most energy efficient because such pathways promote resistance to antimicrobial agents and also because host-imposed deprivation of specific nutrients may hinder the operation of certain pathways. We propose that metabolic prioritization by bacteria underlies the pathogenic outcome of an infection.
    Keywords:  CRP; PTS; PhoP; Salmonella; cAMP; carbon; central metabolism; magnesium; virulence
    DOI:  https://doi.org/10.1128/mmbr.00198-22
  37. Nat Microbiol. 2023 Jun 29.
    Parabacteroides distasonis uses dietary inulin to suppress NASH via its metabolite pentadecanoic acid.
    Wenchao Wei, Chi Chun Wong, Zhongjun Jia, Weixin Liu, Changan Liu, Fenfen Ji, Yasi Pan, Feixue Wang, Guoping Wang, Liuyang Zhao, Eagle S H Chu, Xiang Zhang, Joseph J Y Sung, Jun Yu.
      Non-alcoholic steatohepatitis (NASH) is the severe form of non-alcoholic fatty liver disease, and is characterized by liver inflammation and fat accumulation. Dietary interventions, such as fibre, have been shown to alleviate this metabolic disorder in mice via the gut microbiota. Here, we investigated the mechanistic role of the gut microbiota in ameliorating NASH via dietary fibre in mice. Soluble fibre inulin was found to be more effective than insoluble fibre cellulose to suppress NASH progression in mice, as shown by reduced hepatic steatosis, necro-inflammation, ballooning and fibrosis. We employed stable isotope probing to trace the incorporation of 13C-inulin into gut bacterial genomes and metabolites during NASH progression. Shotgun metagenome sequencing revealed that the commensal Parabacteroides distasonis was enriched by 13C-inulin. Integration of 13C-inulin metagenomes and metabolomes suggested that P. distasonis used inulin to produce pentadecanoic acid, an odd-chain fatty acid, which was confirmed in vitro and in germ-free mice. P. distasonis or pentadecanoic acid was protective against NASH in mice. Mechanistically, inulin, P. distasonis or pentadecanoic acid restored gut barrier function in NASH models, which reduced serum lipopolysaccharide and liver pro-inflammatory cytokine expression. Overall this shows that gut microbiota members can use dietary fibre to generate beneficial metabolites to suppress metabolic disease.
    DOI:  https://doi.org/10.1038/s41564-023-01418-7
  38. Allergy. 2023 Jun 29.
    JPH203, a LAT1 inhibitor, alleviates steroid-resistant murine airway inflammation mediated by Th17 cells.
    Keitaro Hayashi, Mayumi Saeki, Kento Miura, Norimasa Yamasaki, Masaya Matsuda, Hayato Shimora, Takeshi Nabe, Yasuo Shimizu, Tomoe Fujita, Hitoshi Endou, Osamu Kaminuma.
      
    Keywords:  JPH203; L-type amino acid transporter 1 (LAT1); amino acid transporter; immunosuppressant; intractable asthma
    DOI:  https://doi.org/10.1111/all.15798
  39. Pharmaceuticals (Basel). 2023 May 31. pii: 822. [Epub ahead of print]16(6):
    Adenylosuccinic Acid: An Orphan Drug with Untapped Potential.
    Emma Rybalka, Stephanie Kourakis, Charles A Bonsett, Behzad Moghadaszadeh, Alan H Beggs, Cara A Timpani.
      Adenylosuccinic acid (ASA) is an orphan drug that was once investigated for clinical application in Duchenne muscular dystrophy (DMD). Endogenous ASA participates in purine recycling and energy homeostasis but might also be crucial for averting inflammation and other forms of cellular stress during intense energy demand and maintaining tissue biomass and glucose disposal. This article documents the known biological functions of ASA and explores its potential application for the treatment of neuromuscular and other chronic diseases.
    Keywords:  ADSSL1 myopathy; Duchenne muscular dystrophy; Nrf2 activation; adenylosuccinate; adenylosuccinic acid; immunometabolism; metabolic disease; purine metabolism; skeletal muscle; succinyl-AMP
    DOI:  https://doi.org/10.3390/ph16060822
  40. Elife. 2023 Jun 30. pii: e85872. [Epub ahead of print]12
    A back-door insights into the modulation of Src kinase activity by the polyamine spermidine.
    Sofia Rossini, Marco Gagaro, Giulia Scalisi, Elisa Bianconi, Sara Ambrosino, Eleonora Panfili, Claudia Volpi, Ciriana Orabona, Antonio Macchiarulo, Francesca Fallarino, Giada Mondanelli.
      Src is a protein tyrosine kinase commonly activated downstream of transmembrane receptors and plays key roles in cell growth, migration and survival signaling pathways. In conventional dendritic cells (cDCs), Src is involved in the activation of the non-enzymatic functions of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoregulatory molecule endowed with both catalytic activity and signal transducing properties. Prompted by the discovery that the metabolite spermidine confers a tolerogenic phenotype on cDCs that is dependent on both the expression of IDO1 and the activity of Src kinase, we here investigated the spermidine mode of action. We found that spermidine directly binds Src in a previously unknown allosteric site located on the backside of the SH2 domain and thus acts as a positive allosteric modulator of the enzyme. Besides confirming that Src phosphorylates IDO1, here we showed that spermidine promotes the protein-protein interaction of Src with IDO1. Overall, this study may pave the way toward the design of allosteric modulators able to switch on/off the Src-mediated pathways, including those involving the immunoregulatory protein IDO1.
    Keywords:  biochemistry; chemical biology; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.85872
  41. PeerJ. 2022 ;10 e14570
    Effect of hyperglycemia on the immune function of COVID-19 patients with type 2 diabetes mellitus: a retrospective study.
    Ye Wang, Bo Yi, Shujun Wang, Xiaolin Chen, Zhongyuan Wen.
      Purpose: To analyze the clinical characteristics and immune function parameters and to explore the effect of hyperglycemia on the immune function in patients with Corona Virus Disease 2019 (COVID-19) with type 2 diabetes mellitus (T2DM).Methods: This retrospective study included patients with COVID-19 with T2DM hospitalized in Renmin Hospital of Wuhan University between January 31, 2020, and February 10, 2020. The clinical data were collected and patients were divided into a well-controlled group (blood glucose 3.9-10.0 mmol/L) and a poorly-controlled group (blood glucose >10.0 mmol/L). The differences in routine blood tests, peripheral lymphocyte subsets, humoral immune components, C-reactive protein (CRP) level, and cytokines were compared, and the correlation between blood glucose and immune parameters as well as the severity of the disease was analyzed.
    Results: A total of 65 patients with COVID-19 and T2DM were included in the final analysis. Compared with the well-controlled group, patients in the poorly-controlled group had decreased lymphocytes, CD16+ 56+ NK cells, CD3+ T cells, CD8+ T cells and increased neutrophil percentage, IL-6 levels, CRP levels and serum concentration of IgA. Blood glucose was inversely correlated with CD16+ 56+ NK cells, CD3+ T cells, CD4+ T cells, and CD8+ T cells and positively correlated with IL-6 and CRP levels. There was a positive correlation between blood glucose and the severity of the COVID-19.
    Conclusion: Hyperglycemia will aggravate the immune dysfunction of COVID-19 patients with T2DM and affect the severity of COVID-19.
    Keywords:  Corona Virus Disease 2019; Hyperglycemia; Immune function; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.7717/peerj.14570
  42. Nat Commun. 2023 Jun 30. 14(1): 3870
    Single cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome.
    Tim Flerlage, Jeremy Chase Crawford, E Kaitlynn Allen, Danielle Severns, Shaoyuan Tan, Sherri Surman, Granger Ridout, Tanya Novak, Adrienne Randolph, Alina N West, Paul G Thomas.
      Acute respiratory distress syndrome (ARDS), termed pediatric ARDS (pARDS) in children, is a severe form of acute respiratory failure (ARF). Pathologic immune responses are implicated in pARDS pathogenesis. Here, we present a description of microbial sequencing and single cell gene expression in tracheal aspirates (TAs) obtained longitudinally from infants with ARF. We show reduced interferon stimulated gene (ISG) expression, altered mononuclear phagocyte (MNP) transcriptional programs, and progressive airway neutrophilia associated with unique transcriptional profiles in patients with moderate to severe pARDS compared to those with no or mild pARDS. We additionally show that an innate immune cell product, Folate Receptor 3 (FOLR3), is enriched in moderate or severe pARDS. Our findings demonstrate distinct inflammatory responses in pARDS that are dependent upon etiology and severity and specifically implicate reduced ISG expression, altered macrophage repair-associated transcriptional programs, and accumulation of aged neutrophils in the pathogenesis of moderate to severe pARDS caused by RSV.
    DOI:  https://doi.org/10.1038/s41467-023-39593-0
  43. mSystems. 2023 Jun 30. e0126522
    Transcriptome-guided metabolic network analysis reveals rearrangements of carbon flux distribution in Neisseria gonorrhoeae during neutrophil co-culture.
    Aimee D Potter, Christopher M Baiocco, Jason A Papin, Alison K Criss.
      The ability of bacterial pathogens to metabolically adapt to the environmental conditions of their hosts is critical to both colonization and invasive disease. Infection with Neisseria gonorrhoeae (the gonococcus, Gc) is characterized by the influx of neutrophils [polymorphonuclear leukocytes (PMNs)], which fail to clear the bacteria and make antimicrobial products that can exacerbate tissue damage. The inability of the human host to clear Gc infection is particularly concerning in light of the emergence of strains that are resistant to all clinically recommended antibiotics. Bacterial metabolism represents a promising target for the development of new therapeutics against Gc. Here, we generated a curated genome-scale metabolic network reconstruction (GENRE) of Gc strain FA1090. This GENRE links genetic information to metabolic phenotypes and predicts Gc biomass synthesis and energy consumption. We validated this model with published data and in new results reported here. Contextualization of this model using the transcriptional profile of Gc exposed to PMNs revealed substantial rearrangements of Gc central metabolism and induction of Gc nutrient acquisition strategies for alternate carbon source use. These features enhanced the growth of Gc in the presence of neutrophils. From these results, we conclude that the metabolic interplay between Gc and PMNs helps define infection outcomes. The use of transcriptional profiling and metabolic modeling to reveal new mechanisms by which Gc persists in the presence of PMNs uncovers unique aspects of metabolism in this fastidious bacterium, which could be targeted to block infection and thereby reduce the burden of gonorrhea in the human population. IMPORTANCE The World Health Organization designated Gc as a high-priority pathogen for research and development of new antimicrobials. Bacterial metabolism is a promising target for new antimicrobials, as metabolic enzymes are widely conserved among bacterial strains and are critical for nutrient acquisition and survival within the human host. Here we used genome-scale metabolic modeling to characterize the core metabolic pathways of this fastidious bacterium and to uncover the pathways used by Gc during culture with primary human immune cells. These analyses revealed that Gc relies on different metabolic pathways during co-culture with human neutrophils than in rich media. Conditionally essential genes emerging from these analyses were validated experimentally. These results show that metabolic adaptation in the context of innate immunity is important to Gc pathogenesis. Identifying the metabolic pathways used by Gc during infection can highlight new therapeutic targets for drug-resistant gonorrhea.
    Keywords:  Neisseria gonorrhoeae; carbon metabolism; genome-scale metabolic network reconstruction; metabolic network analysis; metabolism; neutrophils; transcriptomics
    DOI:  https://doi.org/10.1128/msystems.01265-22
  44. Front Immunol. 2023 ;14 1189953
    Glycolytic enzyme HK2 promotes PD-L1 expression and breast cancer cell immune evasion.
    Jichun Lin, Wenshuo Fang, Zhuo Xiang, Qingqing Wang, Huapeng Cheng, Shimin Chen, Jing Fang, Jia Liu, Qiang Wang, Zhimin Lu, Leina Ma.
      Immune therapies targeting the PD-1/PD-L1 pathway have been employed in the treatment of breast cancer, which requires aerobic glycolysis to sustain breast cancer cells growth. However, whether PD-L1 expression is regulated by glycolysis in breast cancer cells remains to be further elucidated. Here, we demonstrate that glycolytic enzyme hexokinase 2 (HK2) plays a crucial role in upregulating PD-L1 expression. Under high glucose conditions, HK2 acts as a protein kinase and phosphorylates IκBα at T291 in breast cancer cells, leading to the rapid degradation of IκBα and activation of NF-κB, which enters the nucleus and promotes PD-L1 expression. Immunohistochemistry staining of human breast cancer specimens and bioinformatics analyses reveals a positive correlation between HK2 and PD-L1 expression levels, which are inversely correlated with immune cell infiltration and survival time of breast cancer patients. These findings uncover the intrinsic and instrumental connection between aerobic glycolysis and PD-L1 expression-mediated tumor cell immune evasion and underscore the potential to target the protein kinase activity of HK2 for breast cancer treatment.
    Keywords:  HK2; IκBα; NF-κB; PD-L1; breast cancer; immunotherapy; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2023.1189953
This page is being maintained by Thomas Krichel. It was last updated on 2023‒07‒02 at 18:01:05.