bims-imicid 2024-08-11 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒08‒11
nineteen papers selected by
Dylan Ryan, University of Cambridge

Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity.
The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.
AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.
Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay.
Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity.
Monocarboxylate transporter 4 facilitates Mycobacterium tuberculosis survival through NF-κB p65-mediated interleukin-10 production.
CD38 deletion to preserve CAR T cell metabolism and promote functional persistence.
Revisiting the role of hypoxia-inducible factors and nuclear factor erythroid 2-related factor 2 in regulating macrophage inflammation and metabolism.
Ketone bodies rescue T cell impairments induced by low glucose availability.
Influenza A virus infection activates STAT3 to enhance SREBP2 expression, cholesterol biosynthesis, and virus replication.
Respiratory infection with influenza A virus delays remyelination and alters oligodendrocyte metabolism.
Sensing of Liver-Derived Nicotinamide by Intestinal Group 2 Innate Lymphoid Cells Links Liver Cirrhosis and Ulcerative Colitis Susceptibility.
Aryl hydrocarbon receptor confers protection against macrophage pyroptosis and intestinal inflammation through regulating polyamine biosynthesis.
Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
Butyrate Increases Heparin Synthesis and Storage in Human Mast Cells.
The potential role of lung microbiota and lauroylcarnitine in T-cell activation associated with checkpoint inhibitor pneumonitis.
Characterising the urinary acylcarnitine and amino acid profiles of HIV/TB co-infection, using LC-MS metabolomics.
Salmonella Typhimurium exploits host polyamines for assembly of the type 3 secretion machinery.
Targeted saliva metabolomics in Sjögren's syndrome.

Dev Cell. 2024 Aug 03. pii: S1534-5807(24)00448-9. [Epub ahead of print]

Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity.

Chao Chen, Caiyun Liu, Pengkai Sun, Zhenxing Zhang, Zhimin Wang, Ping Liu, Xinjian Li.

  Itaconate is an immunoregulatory metabolite produced by the mitochondrial enzyme immune-responsive gene 1 (IRG1) in inflammatory macrophages. We recently identified an important mechanism by which itaconate is released from inflammatory macrophages. However, it remains unknown whether extracellular itaconate is taken up by non-myeloid cells to exert immunoregulatory functions. Here, we used a custom-designed CRISPR screen to identify the dicarboxylate transporter solute carrier family 13 member 3 (SLC13A3) as an itaconate importer and to characterize the role of SLC13A3 in itaconate-improved hepatic antibacterial innate immunity. Functionally, liver-specific deletion of Slc13a3 impairs hepatic antibacterial innate immunity in vivo and in vitro. Mechanistically, itaconate uptake via SLC13A3 induces transcription factor EB (TFEB)-dependent lysosomal biogenesis and subsequently improves antibacterial innate immunity in mouse hepatocytes. These findings identify SLC13A3 as a key itaconate importer in mouse hepatocytes and will aid in the development of potent itaconate-based antibacterial therapeutics.

Keywords:  SLC13A3; TFEB; antibacterial innate immunity; importer; itaconate; lysosomal biogenesis

DOI:  https://doi.org/10.1016/j.devcel.2024.07.011
Immunity. 2024 Aug 02. pii: S1074-7613(24)00352-2. [Epub ahead of print]

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.

Christopher M Jackson, Ayush Pant, Wikum Dinalankara, John Choi, Aanchal Jain, Ryan Nitta, Eli Yazigi, Laura Saleh, Liang Zhao, Thomas R Nirschl, Christina M Kochel, Brandon Hwa-Lin Bergsneider, Denis Routkevitch, Kisha Patel, Kwang Bog Cho, Stephany Tzeng, Sarah Y Neshat, Young-Hoon Kim, Barbara J Smith, Maria Cecilia Ramello, Elena Sotillo, Xinnan Wang, Jordan J Green, Chetan Bettegowda, Gordon Li, Henry Brem, Crystal L Mackall, Drew M Pardoll, Charles G Drake, Luigi Marchionni, Michael Lim.

  Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

Keywords:  CD8(+) T cell hypofunction; Meteorin-like protein; T cell exhaustion; anti-tumor immunity; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.immuni.2024.07.003
J Cell Biol. 2024 Oct 07. pii: e202401024. [Epub ahead of print]223(10):

AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.

Eline C Brombacher, Thiago A Patente, Alwin J van der Ham, Tijmen J A Moll, Frank Otto, Fenne W M Verheijen, Esther A Zaal, Arnoud H de Ru, Rayman T N Tjokrodirijo, Celia R Berkers, Peter A van Veelen, Bruno Guigas, Bart Everts.

Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity and suggest AMPK as a target to direct DC-driven tolerogenic responses in therapeutic settings.

DOI: https://doi.org/10.1083/jcb.202401024
Cell. 2024 Jul 27. pii: S0092-8674(24)00774-8. [Epub ahead of print]

Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay.

Michael Mihlan, Stefanie Wissmann, Alina Gavrilov, Lukas Kaltenbach, Marie Britz, Kristin Franke, Barbara Hummel, Andrea Imle, Ryo Suzuki, Manuel Stecher, Katharina M Glaser, Axel Lorentz, Peter Carmeliet, Takehiko Yokomizo, Ingo Hilgendorf, Ritwick Sawarkar, Alba Diz-Muñoz, Joerg M Buescher, Gerhard Mittler, Marcus Maurer, Karoline Krause, Magda Babina, Luise Erpenbeck, Marcus Frank, Angelika S Rambold, Tim Lämmermann.

  Neutrophils are sentinel immune cells with essential roles for antimicrobial defense. Most of our knowledge on neutrophil tissue navigation derived from wounding and infection models, whereas allergic conditions remained largely neglected. Here, we analyzed allergen-challenged mouse tissues and discovered that degranulating mast cells (MCs) trap living neutrophils inside them. MCs release the attractant leukotriene B4 to re-route neutrophils toward them, thus exploiting a chemotactic system that neutrophils normally use for intercellular communication. After MC intracellular trap (MIT) formation, neutrophils die, but their undigested material remains inside MC vacuoles over days. MCs benefit from MIT formation, increasing their functional and metabolic fitness. Additionally, they are more pro-inflammatory and can exocytose active neutrophilic compounds with a time delay (nexocytosis), eliciting a type 1 interferon response in surrounding macrophages. Together, our study highlights neutrophil trapping and nexocytosis as MC-mediated processes, which may relay neutrophilic features over the course of chronic allergic inflammation.

Keywords:  allergy; cell-cell interaction; cell-in-cell structures; innate immune response; intravital imaging; leukocyte dynamics; mast cell; neutrophil

DOI:  https://doi.org/10.1016/j.cell.2024.07.014
Nat Immunol. 2024 Aug 05.

Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity.

Rongchuan Zhao, Jiao Yang, Yunjiao Zhai, Hong Zhang, Yuanshuai Zhou, Lei Hong, Detian Yuan, Ruilong Xia, Yanxiang Liu, Jinlin Pan, Shaheryar Shafi, Guohua Shi, Ruobing Zhang, Dingsan Luo, Jinyun Yuan, Dejing Pan, Changgeng Peng, Shiyang Li, Minxuan Sun.

Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/- mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.

DOI: https://doi.org/10.1038/s41590-024-01921-x
iScience. 2024 Aug 16. 27(8): 110238

Monocarboxylate transporter 4 facilitates Mycobacterium tuberculosis survival through NF-κB p65-mediated interleukin-10 production.

Yingqi Huang, Rong Li, Shuo Chen, Qi Wang, Zhenyu Han, Yun Liang, Yao Liang, Qianna Li, Lingming Lin, Qian Wen, Chaoying Zhou, Xinying Zhou, Li Ma.

  Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, with the highest single-cause mortality. Monocarboxylate transporter 4 (Mct4) transports intracellular lactate outside, but its role in regulating host immune response against Mtb infection remains unknown. Mct4 expression was upregulated in Mtb-infected macrophages and in patients with TB. Mct4 silencing/deficiency significantly decreased Mtb survival in macrophages and in lungs and spleens of mice, while Mct4 overexpression facilitated Mtb survival in macrophages. Furthermore, Mct4 promoted intracellular lactate transport, nuclear factor κB (NF-κB) p65 activation, and interleukin-10 (IL-10) production upon Mtb infection. Mechanistically, IL-10 silencing and IL-10-neutralizing antibody blocked Mct4 overexpressing increased Mtb survival. Replenishing lactate and NF-κB p65 inhibitor JSH23 treatment could inhibit Mct4 overexpressing increased NF-κB p65 activation, IL-10 production, and Mtb survival in macrophages. This study demonstrates that Mct4 promotes Mtb survival through restricting intracellular lactate accumulation to promote NF-κB p65-mediated IL-10 production and suggests Mct4-NF-κB p65-IL-10 axis a potential target for TB treatment.

Keywords:  Immunology; Microbiology

DOI:  https://doi.org/10.1016/j.isci.2024.110238
Mol Ther Oncol. 2024 Sep 19. 32(3): 200847

CD38 deletion to preserve CAR T cell metabolism and promote functional persistence.

Viviana Rubino, Prasad S Adusumilli, Undrakh Ganbaatar.

DOI: https://doi.org/10.1016/j.omton.2024.200847
Front Cell Infect Microbiol. 2024 ;14 1403915

Revisiting the role of hypoxia-inducible factors and nuclear factor erythroid 2-related factor 2 in regulating macrophage inflammation and metabolism.

Kenneth K Y Ting.

  The recent birth of the immunometabolism field has comprehensively demonstrated how the rewiring of intracellular metabolism is critical for supporting the effector functions of many immune cell types, such as myeloid cells. Among all, the transcriptional regulation mediated by Hypoxia-Inducible Factors (HIFs) and Nuclear factor erythroid 2-related factor 2 (NRF2) have been consistently shown to play critical roles in regulating the glycolytic metabolism, redox homeostasis and inflammatory responses of macrophages (Mφs). Although both of these transcription factors were first discovered back in the 1990s, new advances in understanding their function and regulations have been continuously made in the context of immunometabolism. Therefore, this review attempts to summarize the traditionally and newly identified functions of these transcription factors, including their roles in orchestrating the key events that take place during glycolytic reprogramming in activated myeloid cells, as well as their roles in mediating Mφ inflammatory responses in various bacterial infection models.

Keywords:  HIF-1a hypoxia-inducible factor-1a; LPS; NADPH; NRF2; immunometabolism; inflammation; macrophage; redox

DOI:  https://doi.org/10.3389/fcimb.2024.1403915
Eur J Nutr. 2024 Aug 06.

Ketone bodies rescue T cell impairments induced by low glucose availability.

Arianna Ferrari, Jessica Filoni, Carla Di Dedda, Lorenzo Piemonti, Paolo Monti.

  PURPOSE: Ketogenic diets are proposed as a therapeutic approach for type 1 and type 2 diabetes due to their low glucose intake. However, their potential effects on the immune system need investigation. This study aims to explore how glucose concentration and beta-hydroxybutyrate (BHB) impact T cell phenotype, metabolism, and function, with a focus on systemic inflammatory response (T2D) and autoimmunity (T1D).METHODS: T cells from healthy donors were cultured in vitro under varying glucose concentrations with or without BHB. Flow cytometry was employed to analyze changes in T cell phenotype, while proliferation was evaluated through a CFSE dilution assay. Additionally, we used a novel flow cytometry method allowing a direct assessment of T cell metabolism.
RESULTS: Culturing T cells in low glucose concentrations revealed their dependency on glucose metabolism, leading to reduced proliferation rates, overexpression of exhaustion markers and increased susceptibility to Treg suppression and the influence of immune-modulating drugs such as rapamycin, FK506, and MMF. Notably, T cells cultured in low glucose concentrations increased the expression of BDH1 to utilize BHB as an alternative fuel source. Finally, the addition of BHB to the culture effectively rescued T cell impairments caused by insufficient glucose levels.
CONCLUSIONS: T cells display limited capacity to adapt to low glucose levels, resulting in profound functional impairment. However, T cell functions can be efficiently recovered by the presence of 2mM BHB.

Keywords:  Immunometabolism; Ketogenic diet; T cells; Type 1 diabetes

DOI:  https://doi.org/10.1007/s00394-024-03469-w
iScience. 2024 Aug 16. 27(8): 110424

Influenza A virus infection activates STAT3 to enhance SREBP2 expression, cholesterol biosynthesis, and virus replication.

Jingting Zhang, Yunhan Wu, Yujie Wang, Penggang Liu, Kaituo Liu, Jing Sun, Pinghu Zhang, Xiaoquan Wang, Xiufan Liu, Xiulong Xu.

  Cellular cholesterol plays an important role in influenza A virus (IAV) endocytosis and replication. However, how IAV infection regulates cholesterol biosynthesis remains poorly understood. Here, we report that IAV infection activates SREBP2 and induces the expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis pathway. SREBP2 deficiency suppresses IAV-induced HMGCR expression and virus replication. Mechanistically, IAV infection activates JAK2 and STAT3, inhibition of JAK2 and STAT3 activity by their inhibitors or by gene knockout downregulates IAV-induced SREBP2 and HMGCR expression and IAV replication, reduces the content of cellular cholesterol and virus binding to host cells. Exogenous cholesterol reverses the inhibitory effect of S3I-201 and STAT3 deficiency on virus replication. STAT3 or JAK2 overexpression increases the expression of SREBP2 and its downstream target genes, leading to increased IAV replication. These observations collectively suggest that STAT3 activation facilitates IAV replication by inducing SREBP2 expression and increasing cholesterol biosynthesis.

Keywords:  Genetics; Virology

DOI:  https://doi.org/10.1016/j.isci.2024.110424
iScience. 2024 Aug 16. 27(8): 110464

Respiratory infection with influenza A virus delays remyelination and alters oligodendrocyte metabolism.

Allison Y Louie, Jenny Drnevich, Jennifer L Johnson, Meagan Woodard, Anna V Kukekova, Rodney W Johnson, Andrew J Steelman.

  Peripheral viral infection disrupts oligodendrocyte (OL) homeostasis such that endogenous remyelination may be affected. Here, we demonstrate that influenza A virus infection perpetuated a demyelination- and disease-associated OL phenotype following cuprizone-induced demyelination that resulted in delayed OL maturation and remyelination in the prefrontal cortex. Furthermore, we assessed cellular metabolism ex vivo, and found that infection altered brain OL and microglia metabolism in a manner that opposed the metabolic profile induced by remyelination. Specifically, infection increased glycolytic capacity of OLs and microglia, an effect that was recapitulated by lipopolysaccharide (LPS) stimulation of mixed glia cultures. In contrast, mitochondrial dependence was increased in OLs during remyelination, which was similarly observed in OLs of myelinating P14 mice compared to adult and aged mice. Collectively, our data indicate that respiratory viral infection is capable of suppressing remyelination, and suggest that metabolic dysfunction of OLs is implicated in remyelination impairment.

Keywords:  cellular neuroscience; molecular neuroscience; neuroscience; omics; transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.110464
Adv Sci (Weinh). 2024 Aug 09. e2404274

Sensing of Liver-Derived Nicotinamide by Intestinal Group 2 Innate Lymphoid Cells Links Liver Cirrhosis and Ulcerative Colitis Susceptibility.

Jing Shen, Zhen Li, Xiaoyu Liu, Mengqi Zheng, Peng Zhang, Yatai Chen, Qiuheng Tian, Wenyu Tian, Guanjun Kou, Yanyan Cui, Bowen Xu, Yunjiao Zhai, Weijia Li, Xiaohuan Guo, Ju Qiu, Chunyang Li, Ran He, Lixiang Li, Chunhong Ma, Yanqing Li, Xiuli Zuo, Detian Yuan, Shiyang Li.

  The correlation between liver disease and the progression of ulcerative colitis (UC) has remained elusive. In this study, it demonstrates that liver injury is intricately linked to the heightened severity of UC in patients, and causes more profound intestinal damage during DSS-induced colitis in mice. Metabolomics analysis of plasma from liver cirrhosis patients shows liver injury compromising nicotinamide supply for NAD+ biosynthesis in the intestine. Subsequent investigation identifies intestinal group 2 innate lymphoid cells (ILC2s) are responsible for liver injury-exacerbated colitis. Reconstitution of ILC2s or the restoration of NAD+ metabolism proves effective in relieving liver injury-aggravated experimental colitis. Mechanistically, the NAD+ salvage pathway regulates gut ILC2s in a cell-intrinsic manner by supporting the generation of succinate, which fuels the electron transport chain to sustaining ILC2s function. This research deepens the understanding of cellular and molecular mechanisms in liver disease-UC interplay, identifying a metabolic target for innovative treatments in liver injury-complicated colitis.

Keywords:  NAD+ metabolism; group 2 innate lymphoid cells; liver injury; liver‐gut axis; nicotinamide phosphoribosyltransferase; ulcerative colitis

DOI:  https://doi.org/10.1002/advs.202404274
Theranostics. 2024 ;14(11): 4218-4239

Aryl hydrocarbon receptor confers protection against macrophage pyroptosis and intestinal inflammation through regulating polyamine biosynthesis.

Yajing Gao, Kwei-Yan Liu, Wenfeng Xiao, Xueru Xie, Qiuyan Liang, Zikun Tu, Lan Yang, Hongmiao Yu, Haiyan Guo, Saihua Huang, Xiao Han, Jinrong Fu, Yufeng Zhou.

  Rationale: The aryl hydrocarbon receptor (AhR) functions in the regulation of intestinal inflammation, but knowledge of the underlying mechanisms in innate immune cells is limited. Here, we investigated the role of AhR in modulating the functions of macrophages in inflammatory bowel disease pathogenesis. Methods: The cellular composition of intestinal lamina propria CD45+ leukocytes in a dextran sulfate sodium (DSS)-induced mouse colitis model was determined by single-cell RNA sequencing. Macrophage pyroptosis was quantified by analysis of lactate dehydrogenase release, propidium iodide staining, enzyme-linked immunosorbent assay, western blot, and flow cytometry. Differentially expressed genes were confirmed by RNA-seq, RT-qPCR, luciferase assay, chromatin immunoprecipitation, and immunofluorescence staining. Results: AhR deficiency mediated dynamic remodeling of the cellular composition of intestinal lamina propria (LP) CD45+ immune cells in a colitis model, with a significant increase in monocyte-macrophage lineage. Mice with AhR deficiency in myeloid cells developed more severe dextran sulfate sodium induced colitis, with concomitant increased macrophage pyroptosis. Dietary supplementation with an AhR pre-ligand, indole-3-carbinol, conferred protection against colitis while protection failed in mice lacking AhR in myeloid cells. Mechanistically, AhR signaling inhibited macrophage pyroptosis by promoting ornithine decarboxylase 1 (Odc1) transcription, to enhance polyamine biosynthesis. The increased polyamine, particularly spermine, inhibited NLRP3 inflammasome assembly and subsequent pyroptosis by suppressing K+ efflux. AHR expression was positively correlated with ODC1 in intestinal mucosal biopsies from patients with ulcerative colitis. Conclusions: These findings suggest a functional role for the AhR/ODC1/polyamine axis in maintaining intestinal homeostasis, providing potential targets for treatment of inflammatory bowel disease.

Keywords:  Aryl hydrocarbon receptor; ODC1; macrophage; pyroptosis; spermine

DOI:  https://doi.org/10.7150/thno.95749
Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00278-X. [Epub ahead of print]

Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.

Yiming Zhang, Cassandra B Higgins, Stefani Tica, Joshua A Adams, Jiameng Sun, Shannon C Kelly, Xiaoyu Zong, Dennis J Dietzen, Terri Pietka, Samuel J Ballentine, Leah Shriver, Gary Patti, Yin Cao, Brian J DeBosch.

  Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.

Keywords:  arginase; diabetes; fasting; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; nicotinamide adenine dinucleotide; nicotinamide riboside; obesity; tricarboxylic acid cycle; urea cycle

DOI:  https://doi.org/10.1016/j.cmet.2024.07.007
Cells. 2024 Jul 24. pii: 1241. [Epub ahead of print]13(15):

Butyrate Increases Heparin Synthesis and Storage in Human Mast Cells.

Syed Benazir Alam, Zhimin Yan, Nishita Hiresha Verma, Larry D Unsworth, Marianna Kulka.

  Sulphated glycosaminoglycans (GAGs) such as heparin are a major component of mast cell granules and form the matrix within which biogenic mediators are stored. Since GAGs released from mast cells also play an important role in helminth expulsion, understanding GAG storage can offer new insights into mast cell function. Sodium butyrate (NaBu), a short-chain fatty acid, causes ultrastructural changes within the granules of human mast cells (HMC-1) and increases their histamine content. Therefore, we hypothesized that NaBu treatment would also modify the storage of polysaccharides such as GAGs. NaBu (1 mM) significantly increased GAG content and granularity in a time- and concentration-dependent manner without affecting cell viability and metabolic activity. NaBu increased the expression of enzymes associated with heparin biosynthesis (GLCE, NDST1, NDST2, HS6ST1, and GALT1) in a time-dependent manner. A cholesteryl butyrate emulsion (CholButE) increased heparin content after 24 and 48 h and modestly altered the expression of genes involved in heparin biosynthesis. Similar to NaBu, CholButE reduced cell proliferation without significantly altering viability or metabolic activity. These data show that butyrate increases the synthesis and storage of heparin in human mast cells, perhaps by altering their metabolic pathways.

Keywords:  berberine; butyrate; heparin; mast cells; sulfated glycosaminoglycan

DOI:  https://doi.org/10.3390/cells13151241
EBioMedicine. 2024 Aug 03. pii: S2352-3964(24)00303-7. [Epub ahead of print]106 105267

The potential role of lung microbiota and lauroylcarnitine in T-cell activation associated with checkpoint inhibitor pneumonitis.

Wenyi Yu, Keqiang Wang, Yukun He, Ying Shang, Xiaoyi Hu, Xinwei Deng, Lili Zhao, Xinqian Ma, Xinlin Mu, Ran Li, Zhancheng Gao.

  BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event characterized by new pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitor therapy. This study aims to explore the interplay between lung microbiota, dysregulated metabolites, and host immunity in CIP.METHODS: We recruited thirteen hospitalized CIP patients, eleven idiopathic pulmonary fibrosis (IPF) patients, and ten new-onset non-small cell lung cancer patients. Bronchoalveolar lavage fluid samples were collected for 16S rRNA gene sequencing. The percentages of immune cells were determined using manual counting and flow cytometry. Interactions among microbiota, metabolites, and lymphocytes were analyzed using cultured mouse splenocytes and human T cells.
FINDINGS: Proteobacteria emerged as the dominant phylum, notably abundant in both the CIP and IPF groups. Vibrio, Halomonas, Mangrovibacter, and Salinivibrio were the predominant microbiota because of their discriminative abundance patterns. Vibrio (r = 0.72, P-adj = 0.007) and Halomonas (r = 0.65, P-adj = 0.023) demonstrated strong correlations with lymphocytes. Vibrio metschnikovii and Mangrovibacter plantisponsors were more abundant in the CIP group than in the IPF group. Lauroylcarnitine, a key intermediary metabolite co-occurring with the predominant microbiota, exhibited a potent effect on cytokine secretion by mouse and human T cells, notably enhancing IFN-γ and TNF-α production from CD4 and CD8 cells in vitro.
INTERPRETATION: Lauroylcarnitine, co-occurring with the predominant lung microbiota in CIP, could activate T cells in vitro. These findings suggest potential involvement of lung microbiota and acylcarnitine metabolism dysregulation in the pathogenesis of CIP.
FUNDING: This work was supported by Peking University People's Hospital Scientific Research Development Funds (RDJ2022-15) and Provincial Key Clinical Specialty Capacity Building Project 2020 (Department of the Respiratory Medicine).

Keywords:  16S rRNA; Checkpoint inhibitor pneumonitis; Lauroylcarnitine; Lymphocyte; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.ebiom.2024.105267
Metabolomics. 2024 Aug 03. 20(5): 92

Characterising the urinary acylcarnitine and amino acid profiles of HIV/TB co-infection, using LC-MS metabolomics.

Charles Pretorius, Laneke Luies.

  INTRODUCTION: The human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection presents significant challenges due to the complex interplay between these diseases, leading to exacerbated metabolic disturbances. Understanding these metabolic profiles is crucial for improving diagnostic and therapeutic approaches.OBJECTIVE: This study aimed to characterise the urinary acylcarnitine and amino acid profiles, including 5-hydroxyindoleacetic acid (5-HIAA), in patients co-infected with HIV and TB using targeted liquid chromatography mass spectrometry (LC-MS) metabolomics.
METHODS: Urine samples, categorised into HIV, TB, HIV/TB co-infected, and healthy controls, were analysed using HPLC-MS/MS. Statistical analyses included one-way ANOVA and a Kruskal-Wallis test to determine significant differences in the acylcarnitine and amino acid profiles between groups.
RESULTS: The study revealed significant metabolic alterations, especially in TB and co-infected groups. Elevated levels of medium-chain acylcarnitines indicated increased fatty acid oxidation, commonly associated with cachexia in TB. Altered amino acid profiles suggested disruptions in protein and glucose metabolism, indicating a shift towards diabetes-like metabolic states. Notably, TB was identified as a primary driver of these changes, affecting protein turnover, and impacting energy metabolism in co-infected patients.
CONCLUSION: The metabolic profiling of HIV/TB co-infection highlights the profound impact of TB on metabolic pathways, which may exacerbate the clinical complexities of co-infection. Understanding these metabolic disruptions can guide the development of targeted treatments and improve management strategies, ultimately enhancing the clinical outcomes for these patients. Further research is required to validate these findings and explore their implications in larger, diverse populations.

Keywords:  5-HIAA; Acylcarnitines; Amino acids; HIV/TB co-infection; LC–MS; Metabolomics

DOI:  https://doi.org/10.1007/s11306-024-02161-8
PLoS Biol. 2024 Aug;22(8): e3002731

Salmonella Typhimurium exploits host polyamines for assembly of the type 3 secretion machinery.

Tsuyoshi Miki, Takeshi Uemura, Miki Kinoshita, Yuta Ami, Masahiro Ito, Nobuhiko Okada, Takemitsu Furuchi, Shin Kurihara, Takeshi Haneda, Tohru Minamino, Yun-Gi Kim.

Bacterial pathogens utilize the factors of their hosts to infect them, but which factors they exploit remain poorly defined. Here, we show that a pathogenic Salmonella enterica serovar Typhimurium (STm) exploits host polyamines for the functional expression of virulence factors. An STm mutant strain lacking principal genes required for polyamine synthesis and transport exhibited impaired infectivity in mice. A polyamine uptake-impaired strain of STm was unable to inject effectors of the type 3 secretion system into host cells due to a failure of needle assembly. STm infection stimulated host polyamine production by increasing arginase expression. The decline in polyamine levels caused by difluoromethylornithine, which inhibits host polyamine production, attenuated STm colonization, whereas polyamine supplementation augmented STm pathogenesis. Our work reveals that host polyamines are a key factor promoting STm infection, and therefore a promising therapeutic target for bacterial infection.

DOI: https://doi.org/10.1371/journal.pbio.3002731
Clinics (Sao Paulo). 2024 ;pii: S1807-5932(24)00136-4. [Epub ahead of print]79 100459

Targeted saliva metabolomics in Sjögren's syndrome.

Giovanna Piacenza Florezi, Felippe Pereira Barone, Mario Augusto Izidoro, José Maria Soares-Jr, Claudia Malheiros Coutinho-Camillo, Silvia Vanessa Lourenço.

  OBJECTIVE: Sjögren's Syndrome (SS) is a chronic inflammatory autoimmune exocrinopathy, and although, the role of metabolism in the autoimmune responses has been discussed in diseases such as lupus erythematosus, rheumatoid arthritis, psoriasis and scleroderma. There is a lack of information regarding the metabolic implications of SS. Considering that the disease affects primarily salivary glands; the aim of this study is to evaluate the metabolic changes in the salivary glands' microenvironment using a targeted metabolomics approach.METHODS: The saliva from 10 patients diagnosed with SS by the American-European consensus and 10 healthy volunteers was analyzed in an Ultra-high Performance Liquid Chromatograph Coupled Mass Spectrometry (UPLC-MS).
RESULTS: The results showed an increased concentration in SS of metabolites involved in oxidative stress such as lactate, alanine and malate, and amino acids involved in the growth and proliferation of T-cells, such as arginine, leucine valine and isoleucine.
CONCLUSIONS: These results revealed that is possible to differentiate the metabolic profile of SS and healthy individuals using a small amount of saliva, which in its turn may reflect the cellular changes observed in the microenvironments of damaged salivary glands from these patients.

Keywords:  Metabolomics; Saliva; Sjögren's Syndrome

DOI:  https://doi.org/10.1016/j.clinsp.2024.100459