bims-imicid 2024-11-17 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024‒11‒17
thirty-six papers selected by
Dylan Ryan, University of Cambridge

Functional identification of soluble uric acid as an endogenous inhibitor of CD38.
Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism.
Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance.
Itaconate promotes an unexpected tumor immune escape mechanism.
Recent advances in immunometabolism in rheumatic diseases.
Metabolic Regulation of Inflammation: Exploring the Potential Benefits of Itaconate in Autoimmune Disorders.
Macrophage polarization and metabolic reprogramming in abdominal aortic aneurysm.
Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells.
Tragedy of the commons: the resource struggle during Plasmodium infection.
Enhanced ROS Production and Mitochondrial Metabolic Shifts in CD4+ T Cells of an Autoimmune Uveitis Model.
ZDHHC3-mediated SCAP S-acylation promotes cholesterol biosynthesis and tumor immune escape in hepatocellular carcinoma.
Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation.
Ubiquitination in the T Cell Metabolism-Based Immunotherapy in Diseases.
Riboflavin kinase binds and activates inducible nitric oxide synthase to reprogram macrophage polarization.
System-level integrative omics analysis to identify the virus-host immunometabolic footprint during infection.
Esculetin rebalances M1/M2 macrophage polarization to treat sepsis-induced acute lung injury through regulating metabolic reprogramming.
Stearoyl-CoA desaturase in CD4+ T cells suppresses tumor growth through activation of the CXCR3/CXCL11 axis in CD8+ T cells.
Macrophage-Specific Lactate Dehydrogenase Expression Modulates Inflammatory Function In Vitro.
Probiotics and their metabolite spermidine enhance IFN-γ+CD4+ T cell immunity to inhibit hepatitis B virus.
Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness.
Mitochondrial Dysfunction and Metabolic Disturbances Induced by Viral Infections.
Palmitoylcarnitine impairs immunity in decompensated cirrhosis.
Oxidized Low-Density Lipoprotein and Its Role in Immunometabolism.
Microbiota-induced alteration of kynurenine metabolism in macrophages drives formation of creeping fat in Crohn's disease.
Oxidative stress in gut TH17 cells makes mice susceptible to bacterial infection.
Microbial metabolism disrupts cytokine activity to impact host immune response.
Adipokines: masterminds of metabolic inflammation.
Up-regulated succinylation modifications induce a senescence phenotype in microglia by altering mitochondrial energy metabolism.
Effect of Nicotinamide Riboside Against the Exhaustion of CD8+ T Cells via Alleviating Mitochondrial Dysfunction.
Salmonella virulence factors induce amino acid malabsorption in the ileum to promote ecosystem invasion of the large intestine.
Metabolic adaptations of ILC2 and Th2 cells in type 2 immunity.
Post-translational toxin modification by lactate controls Staphylococcus aureus virulence.
Elevated free cholesterol levels due to impaired reverse cholesterol transport are a risk factor for polymicrobial sepsis in mice.
IL-33 Induces a Switch in Intestinal Metabolites Revealing the Tryptophan Pathway as a Target for Inducing Allograft Survival.
A naturally occurring mitochondrial genome variant confers broad protection from infection in Drosophila.
Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.

Elife. 2024 Nov 11. pii: RP96962. [Epub ahead of print]13

Functional identification of soluble uric acid as an endogenous inhibitor of CD38.

Shijie Wen, Hiroshi Arakawa, Shigeru Yokoyama, Yoshiyuki Shirasaka, Haruhiro Higashida, Ikumi Tamai.

  Excessive elevation or reduction of soluble uric acid (sUA) levels has been linked to some of pathological states, raising another subject that sUA at physiological levels may be essential for the maintenance of health. Yet, the fundamental physiological functions and molecular targets of sUA remain largely unknown. Using enzyme assays and in vitro and in vivo metabolic assays, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38 via a reversible non-competitive mechanism, thereby limiting nicotinamide adenine dinucleotide (NAD+) degradation. CD38 inhibition is restricted to sUA in purine metabolism, and a structural comparison using methyl analogs of sUA such as caffeine metabolites shows that 1,3-dihydroimidazol-2-one is the main functional group. Moreover, sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38. Together, this study unveils an unexpected physiological role for sUA in controlling NAD+ availability and innate immunity through CD38 inhibition, providing a new perspective on sUA homeostasis and purine metabolism.

Keywords:  CD38; MSU crystal; gout; hyperuricemia; hypouricemia; immunology; inflammation; metabolism; mouse; nicotinamide adenine dinucleotide; uric acid; uricase

DOI:  https://doi.org/10.7554/eLife.96962
Nat Immunol. 2024 Nov 08.

Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism.

Ronal M Peralta, Bingxian Xie, Konstantinos Lontos, Hector Nieves-Rosado, Kellie Spahr, Supriya Joshi, B Rhodes Ford, Kevin Quann, Andrew T Frisch, Victoria Dean, Mary Philbin, Anthony R Cillo, Sebastian Gingras, Amanda C Poholek, Lawrence P Kane, Dayana B Rivadeneira, Greg M Delgoffe.

CD8+ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (Tex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally Tex cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by Tex cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in Tex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which Tex cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME.

DOI: https://doi.org/10.1038/s41590-024-01999-3
Cancer Cell. 2024 Nov 01. pii: S1535-6108(24)00398-2. [Epub ahead of print]

Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance.

Heng Lin, Kole Tison, Yuheng Du, Paul Kirchhoff, Chan Kim, Weichao Wang, Hannah Yang, Michael Pitter, Jiali Yu, Peng Liao, Jiajia Zhou, Linda Vatan, Sara Grove, Shuang Wei, Thomas Vigil, Yatrik M Shah, Richard Mortensen, Ilona Kryczek, Lana Garmire, Jwala P Sivaccumar, Ashwin Kumar Ramesh, Ningyan Zhang, Zhiqiang An, Shaomeng Wang, Weiping Zou.

  Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discover SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identify a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitize tumors to ferroptosis, curb tumor progression, and bolster ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target for treating SLC13A3+ cancer.

Keywords:  NRF2; SLC13A3; SLC13A3 inhibitor; SLC7A11; T cell immunity; ferroptosis; immune checkpoint blockade; itaconate; macrophages; tumor

DOI:  https://doi.org/10.1016/j.ccell.2024.10.010
Cancer Cell. 2024 Oct 30. pii: S1535-6108(24)00399-4. [Epub ahead of print]

Itaconate promotes an unexpected tumor immune escape mechanism.

Lara Haase, Christian Frezza.

Itaconate is a metabolite produced by macrophages upon infection and acts as an antimicrobial molecule. In this issue of Cancer Cell, Lin et al. found that itaconate produced by tumor-associated macrophages is taken up by cancer cells via the transporter solute carrier family 13 member 3 (SLC13A3), promoting resistance to immune checkpoint inhibitors.

DOI: https://doi.org/10.1016/j.ccell.2024.10.011
Curr Opin Rheumatol. 2024 Nov 08.

Recent advances in immunometabolism in rheumatic diseases.

Ryo Hisada, Michihito Kono.

PURPOSE OF REVIEW: Aberrant autoreactive innate and adaptive immune responses cause systemic autoimmune diseases. Autoimmunity has been linked to abnormal metabolic states, and immunometabolism has emerged as a critical field in understanding the pathogenesis of rheumatic diseases. We aimed to explore the latest research on metabolic reprogramming in various immune cell types, including T cells, B cells, neutrophils, dendritic cells, monocytes, and macrophages, in the context of rheumatic diseases.RECENT FINDINGS: Each immune cell utilizes preferred metabolic pathways, and the cell activation dramatically modifies metabolic status. The inhibition of these pathways alters cell survival, differentiation, proliferation, and cytokine production - all of which contribute to rheumatic disease progression.
SUMMARY: Targeting metabolic pathways or introducing anti-inflammatory metabolites, such as itaconate, could be novel therapeutic strategies for rheumatic diseases. Further research should focus on strategies for translating basic research findings to bedside applications.

DOI: https://doi.org/10.1097/BOR.0000000000001071
Immunology. 2024 Nov 14.

Metabolic Regulation of Inflammation: Exploring the Potential Benefits of Itaconate in Autoimmune Disorders.

Yin Luo, Li-Yan Jiang, Zhe-Zhen Liao, Yuan-Yuan Wang, Ya-Di Wang, Xin-Hua Xiao.

  Itaconic acid and its metabolites have demonstrated significant therapeutic potential in various immune diseases. Originating from the tricarboxylic acid cycle in immune cells, itaconic acid can modulate immune responses, diminish inflammation, and combat oxidative stress. Recent research has uncovered multiple mechanisms through which itaconic acid exerts its effects, including the inhibition of inflammatory cytokine production, activation of anti-inflammatory pathways, and modulation of immune cell function by regulating cellular metabolism. Cellular actions are influenced by the modulation of metabolic pathways, such as inhibiting succinate dehydrogenase (SDH) activity or glycolysis, activation of nuclear-factor-E2-related factor 2 (Nrf2), boosting cellular defences against oxidative stress, and suppression of immune cell inflammation through the NF-κB pathway. This comprehensive review discusses the initiation, progression, and mechanisms of action of itaconic acid and its metabolites, highlighting their modulatory effects on various immune cell types. Additionally, it examines their involvement in immune disease like rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and autoimmune hepatitis, offering greater understanding for creating new therapies for these ailments.

Keywords:  autoimmune disease; itaconic acid; metabolic pathways

DOI:  https://doi.org/10.1111/imm.13875
Immun Inflamm Dis. 2024 Nov;12(11): e1268

Macrophage polarization and metabolic reprogramming in abdominal aortic aneurysm.

Ningxin Hou, Hongmin Zhou, Jun Li, Xiaoxing Xiong, Hongping Deng, Sizheng Xiong.

  BACKGROUND: Abdominal aortic aneurysm (AAA) is a macrovascular disease with high morbidity and mortality in the elderly. The limitation of the current management is that most patients can only be followed up until the AAA diameter increases to a threshold, and surgical intervention is recommended. The development of preventive and curative drugs for AAA is urgently needed. Macrophage-mediated immune inflammation is one of the key pathological links in the occurrence and development of AAA.AIMS: This review article aims to evaluate the impact of immunometabolism on macrophage biology and its role in AAA.
METHODS: We analyze publications focusing on the polarization and metabolic reprogramming in macrophages as well as their potential impact on AAA, and summarize the potential interventions that are currently available to regulate these processes.
RESULTS: The phenotypic and functional changes in macrophages are accompanied by significant alterations in metabolic pathways. The interaction between macrophage polarization and metabolic pathways significantly influences the progression of AAA.
CONCLUSION: Macrophage polarization is a manifestation of the gross dichotomy of macrophage function into pro-inflammatory killing and tissue repair, that is, classically activated M1 macrophages and alternatively activated M2 macrophages. Macrophage functions are closely linked to metabolic changes, and the emerging field of immunometabolism is providing unique insights into the role of macrophages in AAA. It is essential to further investigate the precise metabolic changes and their functional consequences in AAA-associated macrophages.

Keywords:  abdominal aortic aneurysm; inflammation; macrophage polarization; metabolic reprogramming; therapeutic targets

DOI:  https://doi.org/10.1002/iid3.1268
Front Immunol. 2024 ;15 1461455

Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells.

Oliver Goldmann, Eva Medina.

  Myeloid-derived suppressor cells (MDSC) are considered an aberrant population of immature myeloid cells that have attracted considerable attention in recent years due to their potent immunosuppressive activity. These cells are typically absent or present in very low numbers in healthy individuals but become abundant under pathological conditions such as chronic infection, chronic inflammation and cancer. The immunosuppressive activity of MDSC helps to control excessive immune responses that might otherwise lead to tissue damage. This same immunosuppressive activity can be detrimental, particularly in cancer and chronic infection. In the cancer setting, tumors can secrete factors that promote the expansion and recruitment of MDSC, thereby creating a local environment that favors tumor progression by inhibiting the effective immune responses against cancer cells. This has made MDSC a target of interest in cancer therapy, with researchers exploring strategies to inhibit their function or reduce their numbers to improve the efficacy of cancer immunotherapies. In the context of chronic infections, MDSC can lead to persistent infections by suppressing protective immune responses thereby preventing the clearance of pathogens. Therefore, targeting MDSC may provide a novel approach to improve pathogen clearance during chronic infections. Ongoing research on MDSC aims to elucidate the exact processes behind their expansion, recruitment, activation and suppressive mechanisms. In this context, it is becoming increasingly clear that the metabolism of MDSC is closely linked to their immunosuppressive function. For example, MDSC exhibit high rates of glycolysis, which not only provides energy but also generates metabolites that facilitate their immunosuppressive activity. In addition, fatty acid metabolic pathways, such as fatty acid oxidation (FAO), have been implicated in the regulation of MDSC suppressive activity. Furthermore, amino acid metabolism, particularly arginine metabolism mediated by enzymes such as arginase-1, plays a critical role in MDSC-mediated immunosuppression. In this review, we discuss the metabolic signature of MDSC and highlight the therapeutic implications of targeting MDSC metabolism as a novel approach to modulate their immunosuppressive functions.

Keywords:  immunosuppression; infection; metabolic reprogramming; metabolism; myeloid-derived suppressor cells; tumor

DOI:  https://doi.org/10.3389/fimmu.2024.1461455
Trends Parasitol. 2024 Nov 14. pii: S1471-4922(24)00303-9. [Epub ahead of print]

Tragedy of the commons: the resource struggle during Plasmodium infection.

Taylen J Nappi, Noah S Butler.

  Plasmodium spp. have an ancient history with humans, having been described in ancient texts dating back 3500 years ago, which has led to an evolutionary arms race between Plasmodium and humans with Plasmodium successfully subverting durable, sterilizing host immunity. Mechanisms of immune evasion include polymorphism and antigenic variation, as well as dysregulated immune responses, each facilitating transmission and Plasmodium parasite persistence. Notably, metabolite signaling cues in the host and parasite have more recently been appreciated as key drivers for disease progression. Here, we highlight the metabolic interplay between the host and Plasmodium parasites during malaria. We discuss how immunometabolism studies may be leveraged to elucidate this complex relationship and offer opportunities to augment either vaccine- or infection-induced protective immunity.

Keywords:  T helper cells; antibodies; cell metabolism, Plasmodium; malaria; pathogenesis

DOI:  https://doi.org/10.1016/j.pt.2024.10.014
Int J Mol Sci. 2024 Oct 26. pii: 11513. [Epub ahead of print]25(21):

Enhanced ROS Production and Mitochondrial Metabolic Shifts in CD4+ T Cells of an Autoimmune Uveitis Model.

Ronja Söth, Anne L C Hoffmann, Cornelia A Deeg.

  Equine recurrent uveitis (ERU) is a spontaneously occurring autoimmune disease and one of the leading causes of blindness in horses worldwide. Its similarities to autoimmune-mediated uveitis in humans make it a unique spontaneous animal model for this disease. Although many aspects of ERU pathogenesis have been elucidated, it remains not fully understood and requires further research. CD4+ T cells have been a particular focus of research. In a previous study, we showed metabolic alterations in CD4+ T cells from ERU cases, including an increased basal oxygen consumption rate (OCR) and elevated compensatory glycolysis. To further investigate the underlying reasons for and consequences of these metabolic changes, we quantified reactive oxygen species (ROS) production in CD4+ T cells from ERU cases and compared it to healthy controls, revealing significantly higher ROS production in ERU-affected horses. Additionally, we aimed to define mitochondrial fuel oxidation of glucose, glutamine, and long-chain fatty acids (LCFAs) and identified significant differences between CD4+ T cells from ERU cases and controls. CD4+ T cells from ERU cases showed a lower dependency on mitochondrial glucose oxidation and greater metabolic flexibility for the mitochondrial oxidation of glucose and LCFAs, indicating an enhanced ability to switch to alternative fuels when necessary.

Keywords:  CD4+ T cell; autoimmune uveitis; autoimmunity; equine recurrent uveitis (ERU); immunometabolism; metabolic flexibility; neuroinflammation; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms252111513
Cell Rep. 2024 Nov 09. pii: S2211-1247(24)01313-5. [Epub ahead of print]43(11): 114962

ZDHHC3-mediated SCAP S-acylation promotes cholesterol biosynthesis and tumor immune escape in hepatocellular carcinoma.

Mingzhi Wu, Xiaojun Zhou, Xinyi Zhou, Genxin Wang, Yiqun Zeng, Jun Li, Edward V Prochownik, Fubing Wang, Youjun Li.

  Cholesterol metabolism reprogramming plays essential roles in hepatocellular carcinoma (HCC). However, precisely how cholesterol metabolism is dysregulated is not clear. Here, we show that the palmitoyltransferase ZDHHC3 and depalmitoylase ABHD17A regulate HCC cell cholesterol biosynthesis by dynamically S-acylating SREBP cleavage-activating protein (SCAP). SCAP S-acylation by ZDHHC3 at C264 antagonizes HACE1-mediated SCAP ubiquitination. Intriguingly, SREBP2 transcriptionally upregulates ZDHHC3 to form a positive feedback loop, which explains why negative feedback regulation of SCAP/SREBP2 signaling fails in HCC. Increased cholesterol in the tumor microenvironment (TME) restrains CD4+ T cell cytotoxicity. Hence, the cholesterol metabolism reprogramming and cholesterol level alternation in the TME cooperate to promote HCC development. We identified a small-molecule inhibitor of ZDHHC3 that, combined with anti-PD-1 immunotherapy, inhibited diethyl nitrosamine (DEN)/CCl4-induced HCC growth in mice. ZDHHC3-mediated SCAP S-acylation reprograms cholesterol metabolism and promotes HCC immune escape. ZDHHC3 is thus identified as a rational chemotherapy target for HCC.

Keywords:  CP: Cancer; CP: Metabolism; HCC; SCAP/SREBP2; ZDHHC3; cholesterol metabolism; palmitoylation; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2024.114962
Cell Mol Immunol. 2024 Nov 14.

Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation.

Xianyi Meng, Sahar Asadi-Asadabad, Shan Cao, Rui Song, Zhen Lin, Mohammed Safhi, Yi Qin, Estelle Tcheumi Tactoum, Verena Taudte, Arif Ekici, Dirk Mielenz, Stefan Wirtz, Georg Schett, Aline Bozec.

  Germinal centers where B cells undergo clonal expansion and antibody affinity maturation are hypoxic microenvironments. However, the function of hypoxia-inducible factor (HIF)-1α in immunoglobulin production remains incompletely characterized. Here, we demonstrated that B cells lacking HIF-1α exhibited significantly lower glycolytic metabolism and impaired IgA production. Loss of HIF-1α in B cells affects IgA-producing B-cell differentiation and exacerbates dextran sodium sulfate (DSS)-induced colitis. Conversely, promoting HIF-1α stabilization via a PHD inhibitor roxadustat enhances IgA class switching and alleviates intestinal inflammation. Mechanistically, HIF-1α facilitates IgA class switching through acetyl-coenzyme A (acetyl-CoA) accumulation, which is essential for histone H3K27 acetylation at the Sα region. Consequently, supplementation with acetyl-CoA improved defective IgA production in Hif1a-deficient B cells and limited experimental colitis. Collectively, these findings highlight the critical importance of HIF-1α in IgA class switching and the potential for targeting the HIF-1α-dependent metabolic‒epigenetic axis to treat inflammatory bowel diseases and other inflammatory disorders.

Keywords:  B cells; HIF-1α; Hypoxia; IgA; Intestinal inflammation

DOI:  https://doi.org/10.1038/s41423-024-01233-y
Adv Exp Med Biol. 2024 ;1466 19-34

Ubiquitination in the T Cell Metabolism-Based Immunotherapy in Diseases.

Ke-Qi Fan, Yi-Yuan Li, Jin Jin.

  Metabolism refers to the exchange of matter and energy between the organism and the environment and the self-renewal process of matter and energy in the organism. Metabolic activities in cells provide them with energy and various substrates required for development. Naive T cells differentiate into effector T cells and memory T cells after activation, and this process is accompanied by reprogramming of metabolism-related gene expression. These metabolic changes reflect physiological changes in different stages of T cell activation and differentiation. An increasing number of studies have shown that many autoimmune diseases and organ transplantation are accompanied by disorders and imbalances in T cell metabolism. To treat these diseases, related drugs can be used to regulate T cell activation, differentiation, and function. Therefore, T cell metabolism can serve as a new potential target for regulating immune responses.

Keywords:  Immunotherapy; Metabolism; T cells; Ubiquitination

DOI:  https://doi.org/10.1007/978-981-97-7288-9_2
Redox Biol. 2024 Oct 30. pii: S2213-2317(24)00391-4. [Epub ahead of print]78 103413

Riboflavin kinase binds and activates inducible nitric oxide synthase to reprogram macrophage polarization.

Xiao Shan, Zemin Ji, Baochen Wang, Yanan Zhang, Hongyuan Dong, Weijia Jing, Yanzhao Zhou, Penghui Hu, Yan Cui, Zihan Li, Sujun Yu, Jinxue Zhou, Ting Wang, Long Shen, Yuping Liu, Qiujing Yu.

  Riboflavin kinase (RFK) is essential in riboflavin metabolism, converting riboflavin to flavin mononucleotide (FMN), which is further processed to flavin adenine dinucleotide (FAD). While RFK enhances macrophage phagocytosis of Listeria monocytogenes, its role in macrophage polarization is not well understood. Our study reveals that RFK deficiency impairs M(IFN-γ) and promotes M(IL-4) polarization, both in vitro and in vivo. Mechanistically, RFK interacts with inducible nitric oxide (NO) synthase (iNOS), which requires FMN and FAD as cofactors for activation, leading to increased NO production that alters energy metabolism by inhibiting the tricarboxylic acid cycle and mitochondrial electron transport chain. Exogenous FAD reverses the metabolic and polarization changes caused by RFK deficiency. Furthermore, bone marrow adoptive transfer from high-riboflavin-fed mice into wild-type tumor-bearing mice reprograms tumor-associated macrophage polarization and inhibits tumor growth. These results suggest that targeting RFK-iNOS or modulating riboflavin metabolism could be potential therapies for macrophage-related immune diseases.

Keywords:  Inducible nitric oxide synthase; Macrophage polarization; Riboflavin kinase

DOI:  https://doi.org/10.1016/j.redox.2024.103413
Adv Immunol. 2024 ;pii: S0065-2776(24)00062-2. [Epub ahead of print]164 73-100

System-level integrative omics analysis to identify the virus-host immunometabolic footprint during infection.

Anoop Ambikan, Sara Svensson Akusjärvi, Maike Sperk, Ujjwal Neogi.

  The emergence and re-emergence of infectious diseases present significant global health threats. Understanding their pathogenesis is crucial for developing diagnostics, therapeutics, and preventive strategies. System-level integrative omics analysis offers a comprehensive approach to deciphering virus-host immunometabolic interactions during infections. Multi-omics approaches, integrating genomics, transcriptomics, proteomics, and metabolomics, provide holistic insights into disease mechanisms, host-pathogen interactions, and immune responses. The interplay between the immune system and metabolic processes, termed immunometabolism, has gained attention, particularly in infectious diseases. Immunometabolic studies reveal how metabolic processes regulate immune cell function, shaping immune responses and influencing infection outcomes. Metabolic reprogramming is crucial for immune cell activation, differentiation, and function. Using systems biological algorithms to understand the immunometabolic alterations can provide a holistic view of immune and metabolic pathway interactions, identifying regulatory nodes and predicting responses to perturbations. Understanding these pathways enhances the knowledge of immune regulation and offers avenues for therapeutic interventions. This review highlights the contributions of multi-omics systems biology studies in understanding infectious disease pathogenesis, focusing on RNA viruses. The integrative approach enables personalized medicine strategies, considering individual metabolic and immune variations. Leveraging these interdisciplinary approaches promises advancements in combating RNA virus infections and improving health outcomes, highlighting the transformative impact of multi-omics technologies in infectious disease research.

Keywords:  Integrative omics; genome scale metabolic models; systems biology; virus

DOI:  https://doi.org/10.1016/bs.ai.2024.08.002
J Cell Mol Med. 2024 Nov;28(21): e70178

Esculetin rebalances M1/M2 macrophage polarization to treat sepsis-induced acute lung injury through regulating metabolic reprogramming.

Feng Chen, Ning Wang, Jiabao Liao, Mengxue Jin, Fei Qu, Chengxin Wang, Min Lin, Huantian Cui, Weibo Wen, Fengjuan Chen.

  Sepsis-induced acute lung injury (SALI) is characterized by a high incidence and mortality rate, which has caused a serious medical burden. The pharmacological effects of esculetin (ELT), such as antibacterial and anti-inflammatory actions, have been widely confirmed. However, the therapeutic effects and mechanisms of ELT on SALI still need to be further clarified. In this study, we first evaluated the therapeutic potential of ELT on a caecal ligation and puncture (CLP) induced septic rat model, particularly in the treatment of acute lung injury. Afterwards, we explored the effect of ELT on macrophage polarization in vivo and in vitro. Then, we investigated the anti-inflammatory mechanism of ELT based on modulating the metabolic reprogramming of macrophage (the effect on glycolysis in M1, and the effect on fatty acid β-oxidation in M2). In addition, macrophage metabolic inhibitors (glycolysis inhibitor: 2-DG, and fatty acid β-oxidation inhibitor: etomoxir) were used to verify the regulatory effect of ELT on macrophage metabolic reprogramming. Our results proved that ELT intervention could effectively improve the survival rate of SALI rats and ameliorate pathological injury. Next, we found that ELT intervention inhibited M1 polarization and promoted M2 polarization of macrophages in vivo and in vitro, including the downregulation of M1-related markers (CD86, iNOS), the decrease of pro-inflammatory factors (nitric oxide, IL-1β, IL-6, and TNF-α), the upregulation of M2-related markers (CD206, ARG-1), the increase of immunomodulatory factors (IL-4 and IL-10). Subsequently, seahorse analysis showed that ELT intervention inhibited the glycolytic capacity in M1, and promoted the ability of fatty acid β-oxidation in M2. Besides, ELT intervention inhibited the level of glycolysis product (lactic acid), and the expression of glycolysis-related genes (Glut1, Hk2, Pfkfb1, Pkm and Ldha) and promoted the expression of fatty acid β-oxidation related genes (Cpt1a, Cpt2, Acox1). In addition, we found that the inhibitory effect of ELT on M1 polarization was comparable to that of 2-DG, while intervention with etomoxir abolished the promoting effect of ELT on M2 polarization. ELT inhibited the inflammatory response in SALI by correcting macrophage polarization (inhibiting M1 and promoting M2). The mechanism of ELT on macrophage polarization was associated with regulating metabolic reprogramming (inhibiting glycolysis in M1 and promoting fatty acid β-oxidation in M2).

Keywords:  esculetin; fatty acid β‐oxidation; glycolysis; macrophage polarization; metabolic reprogramming; sepsis‐induced acute lung injury

DOI:  https://doi.org/10.1111/jcmm.70178
Cell Biosci. 2024 Nov 14. 14(1): 137

Stearoyl-CoA desaturase in CD4+ T cells suppresses tumor growth through activation of the CXCR3/CXCL11 axis in CD8+ T cells.

Sung-Hyun Hwang, Yeseul Yang, Jae-Ha Jung, Jin Won Kim, Yongbaek Kim.

  BACKGROUND: Within the tumor microenvironment, altered lipid metabolism promotes cancer cell malignancy by activating oncogenic cascades; however, impact of lipid metabolism in CD4+ tumor-infiltrating lymphocytes (TILs) remains poorly understood. Here, we elucidated that role of stearoyl-CoA desaturase (SCD) increased by treatment with cancer-associated fibroblast (CAF) supernatant in CD4+ T cells on their subset differentiation and activity of CD8+ T cells.RESULTS: In our study, we observed that CD4+ TILs had higher lipid droplet content than CD4+ splenic T cells. In tumor tissue, CAF-derived supernatant provided fatty acids to CD4+ TILs, which increased the expression of SCD and oleic acid (OA) content. Increased SCD expression by OA treatment enhanced the levels of Th1 cell markers TBX21, interleukin-2, and interferon-γ. However, SCD inhibition upregulated the expression of regulatory T (Treg) cell markers, FOXP3 and transforming growth factor-β. Comparative fatty acid analysis of genetically engineered Jurkat cells revealed that OA level was significantly higher in SCD-overexpressing cells. Overexpression of SCD increased expression of Th1 cell markers, while treatment with OA enhanced the transcriptional level of TBX21 in Jurkat cells. In contrast, palmitic acid which is higher in SCD-KO cells than other subclones enhanced the expression of Treg cell markers through upregulation of mitochondrial superoxide. Furthermore, SCD increased the secretion of the C-X-C motif chemokine ligand 11 (CXCL11) from CD4+ T cells. The binding of CXCL11 to CXCR3 on CD8+ T cells augmented their cytotoxic activity. In a mouse tumor model, the suppressive effect of CD8+ T cells on tumor growth was dependent on CXCR3 expression.
CONCLUSION: These findings illustrate that SCD not only orchestrates the differentiation of T helper cells, but also promotes the antitumor activity of CD8+ T cells, suggesting its function in adverse tumor microenvironments.

Keywords:  CD4+ T cell; CD8+ T cell; CXCL11; CXCR3; Immune response; Lipid metabolism; SCD; Tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1186/s13578-024-01308-3
Kidney360. 2024 Nov 12.

Macrophage-Specific Lactate Dehydrogenase Expression Modulates Inflammatory Function In Vitro.

Yan Lu, Gunars Osis, Anna A Zmijewska, Amie Traylor, Saakshi Thukral, Landon Wilson, Stephen Barnes, James F George, Anupam Agarwal.

BACKGROUND: In acute kidney injury, macrophages play a major role in regulating inflammation. Classically activated macrophages (M1) undergo drastic metabolic reprogramming during their differentiation and upregulate the aerobic glycolysis pathway to fulfill their pro-inflammatory functions. NAD+ regeneration is crucial for the maintenance of glycolysis and the most direct pathway by which this occurs is via the fermentation of pyruvate to lactate, catalyzed by lactate dehydrogenase A (LDHA). Our previous study determined that LDHA is predominantly expressed in the proximal segments of the nephron in the mouse kidney and increases with hypoxia. This study investigates the potential of LDHA as a therapeutic target for inflammation by exploring its role in macrophage function in vitro.METHODS: Bone-marrow-derived macrophages (BMDMs) were isolated from myeloid-specific LDHA knockout mice derived from crossbreeding LysM-Cre transgenic mice and LDHA floxed mice. RNA sequencing and LC-MS/MS metabolomics analyses were used in this study to determine the effect of LDHA deletion on BMDM following stimulation with IFN-γ.
RESULTS: LDHA deletion in IFN-γ BMDMs resulted in a significant alteration of the macrophage activation and functional pathways, and change in glycolytic, cytokine, and chemokine gene expression. Metabolite concentrations associated with pro-inflammatory macrophage profiles were diminished while anti-inflammatory-associated ones were increased in LDHA KO BMDMs. Glutamate and amino sugars metabolic pathways were significantly affected by the LDHA deletion. A combined muti-omics analysis highlighted changes in Rap1 signaling, cytokine-cytokine receptor interaction, focal adhesion, and MAPK signaling metabolism pathways.
CONCLUSIONS: Deletion of LDHA in macrophages results in a notable reduction in the pro-inflammatory profile and concurrent upregulation of anti-inflammatory pathways. These findings suggest that LDHA could serve as a promising therapeutic target for inflammation, a key contributor to the pathogenesis of acute kidney injury.

DOI: https://doi.org/10.34067/KID.0000000630
Cell Rep Med. 2024 Nov 07. pii: S2666-3791(24)00593-7. [Epub ahead of print] 101822

Probiotics and their metabolite spermidine enhance IFN-γ+CD4+ T cell immunity to inhibit hepatitis B virus.

Tixiao Wang, Yuchen Fan, Siyu Tan, Zehua Wang, Mengzhen Li, Xiaowei Guo, Xiangguo Yu, Qinghai Lin, Xiaojia Song, Leiqi Xu, Lixiang Li, Shiyang Li, Lifen Gao, Xiaohong Liang, Chunyang Li, Chunhong Ma.

  The therapeutic potential of commensal microbes and their metabolites is promising in the functional cure of chronic hepatitis B virus (HBV) infection, which is defined as hepatitis B surface antigen (HBsAg) loss. Here, using both specific-pathogen-free and germ-free mice, we report that probiotics significantly promote the decline of HBsAg and inhibit HBV replication by enhancing intestinal homeostasis and provoking intrahepatic interferon (IFN)-γ+CD4+ T cell immune response. Depletion of CD4+ T cells or blockage of IFN-γ abolishes probiotics-mediated HBV inhibition. Specifically, probiotics-derived spermidine accumulates in the gut and transports to the liver, where it exhibits a similar anti-HBV effect. Mechanistically, spermidine enhances IFN-γ+CD4+ T cell immunity by autophagy. Strikingly, administration of probiotics in HBV patients reveals a preliminary trend to accelerate the decline of serum HBsAg. In conclusion, probiotics and their derived spermidine promote HBV clearance via autophagy-enhanced IFN-γ+CD4+ T cell immunity, highlighting the therapeutic potential of probiotics and spermidine for the functional cure of HBV patients.

Keywords:  IFN-γ(+)CD4(+) T cell; autophagy; fecal microbiota transplantation; gut microbiota; hepatitis B virus; probiotics; spermidine

DOI:  https://doi.org/10.1016/j.xcrm.2024.101822
Commun Biol. 2024 Nov 10. 7(1): 1484

Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness.

Jianjun Chang, Zijie Li, Hui Yuan, Xuejiao Wang, Jingyi Xu, Pingting Yang, Ling Qin.

Sleepiness is commonly associated with neuroinflammation; however, the underlying neuroregulatory mechanisms remain unclear. Previous research suggests that the paraventricular thalamus (PVT) plays a crucial role in regulating sleep-wake dynamics; thus, neurological abnormalities in the PVT may contribute to neuroinflammation-induced sleepiness. To test this hypothesis, we performed electroencephalography recordings in mice treated with lipopolysaccharide (LPS) and found that the mice exhibited temporary sleepiness lasting for 7 days. Using the Fos-TRAP method, fiber photometry recordings, and immunofluorescence staining, we detected temporary PVT neuron hypoactivation and microglia activation from day 1 to day 7 post-LPS treatment. Combining the results of bulk and single-cell RNA sequencing, we found upregulation of aconitate decarboxylase 1 (Acod1) in PVT microglia post-LPS treatment. To investigate the role of Acod1, we manipulated Acod1 gene expression in PVT microglia via stereotactic injection of short hairpin RNA adenovirus. Knockdown of Acod1 exacerbated inflammation, neuronal hypoactivation, and sleepiness. Itaconate is a metabolite synthesized by the enzyme encoded by Acod1. Finally, we confirmed that exogenous administration of an itaconate derivative, 4-octyl itaconate, could inhibit microglia activation, alleviate neuronal dysfunction, and relieve sleepiness. Our findings highlight PVT's role in inflammation-induced sleepiness and suggest Acod1 as a potential therapeutic target for neuroinflammation.

DOI: https://doi.org/10.1038/s42003-024-07215-0
Cells. 2024 Oct 29. pii: 1789. [Epub ahead of print]13(21):

Mitochondrial Dysfunction and Metabolic Disturbances Induced by Viral Infections.

Sandra E Pérez, Monika Gooz, Eduardo N Maldonado.

  Viruses are intracellular parasites that utilize organelles, signaling pathways, and the bioenergetics machinery of the cell to replicate the genome and synthesize proteins to build up new viral particles. Mitochondria are key to supporting the virus life cycle by sustaining energy production, metabolism, and synthesis of macromolecules. Mitochondria also contribute to the antiviral innate immune response. Here, we describe the different mechanisms involved in virus-mitochondria interactions. We analyze the effects of viral infections on the metabolism of glucose in the Warburg phenotype, glutamine, and fatty acids. We also describe how viruses directly regulate mitochondrial function through modulation of the activity of the electron transport chain, the generation of reactive oxygen species, the balance between fission and fusion, and the regulation of voltage-dependent anion channels. In addition, we discuss the evasion strategies used to avoid mitochondrial-associated mechanisms that inhibit viral replication. Overall, this review aims to provide a comprehensive view of how viruses modulate mitochondrial function to maintain their replicative capabilities.

Keywords:  VDACs; Warburg; electron transport chain; fatty acids; glucose; glutamine; innate immunity; metabolic reprogramming; mitochondria; reactive oxygen species; virus

DOI:  https://doi.org/10.3390/cells13211789
JHEP Rep. 2024 Nov;6(11): 101187

Palmitoylcarnitine impairs immunity in decompensated cirrhosis.

Ingrid Wei Zhang, María Belén Sánchez-Rodríguez, Cristina López-Vicario, Mireia Casulleras, Marta Duran-Güell, Roger Flores-Costa, Ferran Aguilar, Michael Rothe, Paula Segalés, Carmen García-Ruiz, José C Fernández-Checa, Jonel Trebicka, Vicente Arroyo, Joan Clària.

  Background & Aims: In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells.Methods: Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy individuals. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leucocytes from healthy donors by determining mitochondrial membrane potential (Δψm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox systems were assessed by transmission electron microscopy and gene and protein expression analysis.
Results: Plasma levels of several acylcarnitine species were significantly elevated in patients with AD cirrhosis compared with healthy individuals, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, p = 0.0059) impaired Δψm and reduced the spare respiratory capacity of peripheral mononuclear leucocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the expression of the antioxidant gene HMOX1, and increased CXCL8 expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into the mitochondria, reversed the suppression of HMOX1. Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced CXCL8 expression. Importantly, oxidative stress and Δψm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis.
Conclusions: Our findings suggest that long-chain acylcarnitines induce mitochondrial injury in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis.
Impact and implications: Patients with acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings underline the importance of immunometabolism as a treatment target in patients with acute decompensation of cirrhosis and ACLF.

Keywords:  Acute decompensation of cirrhosis; Acylcarnitines; Immune cells; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.jhepr.2024.101187
Int J Mol Sci. 2024 Oct 23. pii: 11386. [Epub ahead of print]25(21):

Oxidized Low-Density Lipoprotein and Its Role in Immunometabolism.

Negin Mosalmanzadeh, Brandt D Pence.

  Modified cholesterols such as oxidized low-density lipoprotein (OxLDL) contribute to atherosclerosis and other disorders through the promotion of foam cell formation and inflammation. In recent years, it has become evident that immune cell responses to inflammatory molecules such as OxLDLs depend on cellular metabolic functions. This review examines the known effects of OxLDL on immunometabolism and immune cell responses in atherosclerosis and several other diseases. We additionally provide context on the relationship between OxLDL and aging/senescence and identify gaps in the literature and our current understanding in these areas.

Keywords:  OxLDL; aging; atherosclerosis; immunology; inflammation; metabolism; senescence

DOI:  https://doi.org/10.3390/ijms252111386
Cell Host Microbe. 2024 Nov 13. pii: S1931-3128(24)00394-9. [Epub ahead of print]32(11): 1927-1943.e9

Microbiota-induced alteration of kynurenine metabolism in macrophages drives formation of creeping fat in Crohn's disease.

Jinjie Wu, Wanyi Zeng, Hongyu Xie, Mujia Cao, Jingyi Yang, Yanchun Xie, Zhanhao Luo, Zongjin Zhang, Haoyang Xu, Weidong Huang, Tingyue Zhou, Jinyu Tan, Xiaomin Wu, Zihuan Yang, Shu Zhu, Ren Mao, Zhen He, Ping Lan.

  Hyperplasia of mesenteric tissues in Crohn's disease, called creeping fat (CrF), is associated with surgical recurrence. Although microbiota translocation and colonization have been found in CrF, convincing mouse phenotypes and the underlying mechanisms of CrF formation remain unclear. Utilizing single-nucleus RNA (snRNA) sequencing of CrF and different mouse models, we demonstrate that the commensal Achromobacter pulmonis induces mesenteric adipogenesis through macrophage alteration. Targeted metabolome analysis reveals that L-kynurenine is the most enriched metabolite in CrF. Upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) enhances kynurenine metabolism and drives mesenteric adipogenesis. Leveraging single-cell RNA (scRNA) sequencing of mouse mesenteric tissues and macrophage-specific IDO1 knockout mice, we verify the role of macrophage-sourced L-kynurenine in mesenteric adipogenesis. Mechanistically, L-kynurenine-induced adipogenesis is mediated by the aryl hydrocarbon receptors in adipocytes. Administration of an IDO1 inhibitor or bacteria engineered to degrade L-kynurenine alleviates mesenteric adipogenesis in mice. Collectively, our study demonstrates that microbiota-induced modulation of macrophage metabolism potentiates CrF formation.

Keywords:  Crohn’s disease; creeping fat; kynurenine; macrophages; microbiota

DOI:  https://doi.org/10.1016/j.chom.2024.10.008
Immunometabolism (Cobham). 2024 Oct;6(4): e00049

Oxidative stress in gut TH17 cells makes mice susceptible to bacterial infection.

Simon O'Shaughnessy, David K Finlay.

  A recent paper published in Cell Metabolism in August 2024 by Dirk Brenner's laboratory highlights the importance of effectively managing reactive oxygen species (ROS) in gut TH17 T cells for minimizing the damage caused by intestinal bacterial infection. This commentary will discuss the control of cellular ROS by glutathione and the emerging understanding that neutralizing ROS in immune cells is essential for the individualized functions of different immune subsets. In the case of this study, managing ROS within TH17 cells in the gut was shown to be essential to sustain the production of IL22 cytokine to maintain gut homeostasis in response to bacterial infection.

Keywords:  CD4; IL17; IL22; TH17; gastrointestinal infection with Citrobacter rodentium; glutamate-cysteine ligase catalytic subunit; glutathione; mTORc1; mitochondria, reactive oxygen species; mitochondrial transcription factor A

DOI:  https://doi.org/10.1097/IN9.0000000000000049
Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2405719121

Microbial metabolism disrupts cytokine activity to impact host immune response.

Eleanor K P Marshall, Catarina Nunes, Sophie Burbaud, Crystal M Vincent, Natalie O Munroe, Carolina J Simoes da Silva, Ashima Wadhawan, William H Pearson, Jasper Sangen, Lucas Boeck, R Andres Floto, Marc S Dionne.

  Host-pathogen interactions are shaped by the metabolic status of both the host and pathogen. The host must regulate metabolism to fuel the immune response, while the pathogen must extract metabolic resources from the host to enable its own survival. In this study, we focus on the metabolic interactions of Mycobacterium abscessus with Drosophila melanogaster. We identify MAB_1132c as an asparagine transporter required for pathogenicity in M. abscessus. We show that this requirement is specifically associated with damage to the host: flies infected with MAB_1132c knockout bacteria, or with wild-type bacteria grown in asparagine-restricted conditions, are longer lived without showing a significant change in bacterial load. This is associated with a reduction in the host innate immune response, demonstrated by the decreased transcription of antimicrobial peptides as well as a significant reduction in the ability of the infection to disrupt systemic insulin signaling. Much of the increase in host survival during infection with asparagine-limited M. abscessus can be attributed to alterations in unpaired cytokine signaling. This demonstrates that asparagine transport in M. abscessus prior to infection is not required for replicative fitness in vivo but does significantly influence the interaction with the host immune responses.

Keywords:  Drosophila melanogaster; Mycobacterium abscessus; infection; innate immunity; metabolism

DOI:  https://doi.org/10.1073/pnas.2405719121
Nat Rev Immunol. 2024 Nov 07.

Adipokines: masterminds of metabolic inflammation.

Herbert Tilg, Gianluca Ianiro, Antonio Gasbarrini, Timon E Adolph.

Adipose tissue is an immunologically active organ that controls host physiology, partly through the release of mediators termed adipokines. In obesity, adipocytes and infiltrating leukocytes produce adipokines, which include the hormones adiponectin and leptin and cytokines such as tumour necrosis factor and IL-1β. These adipokines orchestrate immune responses that are collectively referred to as metabolic inflammation. Consequently, metabolic inflammation characterizes metabolic disorders and promotes distinct disease aspects, such as insulin resistance, metabolic dysfunction-associated liver disease and cardiovascular complications. In this unifying concept, adipokines participate in the immunological cross-talk that occurs between metabolically active organs in metabolic diseases, highlighting the fundamental role of adipokines in obesity and their potential for therapeutic intervention. Here, we summarize how adipokines shape metabolic inflammation in mice and humans, focusing on their contribution to metabolic disorders in the setting of obesity and discussing their value as therapeutic targets.

DOI: https://doi.org/10.1038/s41577-024-01103-8
J Neuroinflammation. 2024 Nov 14. 21(1): 296

Up-regulated succinylation modifications induce a senescence phenotype in microglia by altering mitochondrial energy metabolism.

Xinnan Zhao, Xiaohan Yang, Cong Du, Huimin Hao, Shuang Liu, Gang Liu, Guangyin Zhang, Kai Fan, Jianmei Ma.

  The aging of the central nervous system(CNS) is a primary contributor to neurodegenerative diseases in older individuals and significantly impacts their quality of life. Neuroinflammation, characterized by activation of microglia(MG) and release of cytokines, is closely associated with the onset of these neurodegenerative diseases. The activated status of MG is modulated by specifically programmed metabolic changes under various conditions. Succinylation, a novel post-translational modification(PTM) mainly involved in regulating mitochondrial energy metabolism pathways, remains unknown in its role in MG activation and aging. In the present study, we found that succinylation levels were significantly increased both during aging and upon lipopolysaccharide-induced(LPS-induced) MG activation undergoing metabolic reprogramming. Up-regulated succinylation induced by sirtuin 5 knockdown(Sirt5 KD) in microglial cell line BV2 resulted in significant up-regulation of aging-related genes, accompanied by impaired mitochondrial adaptability and a shift towards glycolysis as a major metabolic pathway. Furthermore, after LPS treatment, Sirt5 KD BV2 cells exhibited increased generation of reactive oxygen species(ROS), accumulation of lipid droplets, and elevated levels of lipid peroxidation. By employing immunoprecipitation, introducing point mutation to critical succinylation sites, and conducting enzyme activity assays for succinate dehydrogenase(SDH) and trifunctional enzyme subunit alpha(ECHA), we demonstrated that succinylation plays a regulatory role in modulating the activities of these mitochondrial enzymes. Finally, down-regulation the succinylation levels achieved through administration of succinyl phosphonate(SP) led to amelioration of MG senescence in vitro and neuroinflammation in vivo. To our knowledge, our data provide preliminary evidence indicating that up-regulated succinylation modifications elicit a senescence phenotype in MG through alterations in energy metabolism. Moreover, these findings suggest that manipulation of succinylation levels may offer valuable insights into the treatment of aging-related neuroinflammation.

Keywords:  Aging; Metabolic reprogramming; Microglia; Neuroinflammation; Succinylation

DOI:  https://doi.org/10.1186/s12974-024-03284-4
Nutrients. 2024 Oct 22. pii: 3577. [Epub ahead of print]16(21):

Effect of Nicotinamide Riboside Against the Exhaustion of CD8+ T Cells via Alleviating Mitochondrial Dysfunction.

Ying Xiao, Nengzhi Pang, Sixi Ma, Mengqi Gao, Lili Yang.

  Background: Targeting mitochondria and protecting the mitochondrial function of CD8+ T cells are crucial for enhancing the clinical efficacy of cancer immunotherapy. Objectives: In this study, our objective was to investigate the potential of nicotinamide riboside (NR) in preserving the mitochondrial function of CD8+ T cells and mitigating their exhaustion. Methods: We established two in vitro models to induce CD8+ T cell exhaustion either by tumor cell-conditioned medium (TCM) or by continuous stimulation with OVA(257-264) peptide. CD8+ T cells were treated in the absence/presence of NR. Results: Our findings demonstrated that NR supplementation effectively inhibited CD8+ T cell exhaustion and preserved mitochondrial function in both models. Moreover, apoptosis of CD8+ T cells was reduced after NR treatment. Western blot data indicated that NR treatment upregulated Silent information regulator 1 (SirT1) expression. Further inhibition of Sirt1 activity using EX527 uncovered that the inhibitory effect of NR on CD8+ T cell exhaustion and its protective effect on mitochondria were attenuated. Conclusions: In conclusion, our results indicate that NR supplementation attenuates CD8+ T cell exhaustion, and its underlying mechanism is associated with increased mitochondrial function regulated by the SirT1 pathway. Our research provides evidence that NR may assist in enhancing the clinical efficacy of immunotherapy.

Keywords:  CD8+ T cells exhaustion; mitochondrial; nicotinamide ribose

DOI:  https://doi.org/10.3390/nu16213577
Proc Natl Acad Sci U S A. 2024 Nov 19. 121(47): e2417232121

Salmonella virulence factors induce amino acid malabsorption in the ileum to promote ecosystem invasion of the large intestine.

Lauren C Radlinski, Andrew W L Rogers, Lalita Bechtold, Hugo L P Masson, Henry Nguyen, Anaïs B Larabi, Connor R Tiffany, Thaynara Parente de Carvalho, Renée M Tsolis, Andreas J Bäumler.

  The gut microbiota produces high concentrations of antimicrobial short-chain fatty acids (SCFAs) that restrict the growth of invading microorganisms. The enteric pathogen Salmonella enterica serovar (S.) Typhimurium triggers inflammation in the large intestine to ultimately reduce microbiota density and bloom, but it is unclear how the pathogen gains a foothold in the homeostatic gut when SCFA-producing commensals are abundant. Here, we show that S. Typhimurium invasion of the ileal mucosa triggers malabsorption of dietary amino acids to produce downstream changes in nutrient availability in the large intestine. In gnotobiotic mice engrafted with a community of 17 human Clostridia isolates, S. Typhimurium virulence factors triggered marked changes in the cecal metabolome, including an elevated abundance of amino acids. In an ex vivo fecal culture model, we found that two of these amino acids, lysine and ornithine, countered SCFA-mediated growth inhibition by restoring S. Typhimurium pH homeostasis through the inducible amino acid decarboxylases CadA and SpeF, respectively. In a mouse model of gastrointestinal infection, S. Typhimurium CadA activity depleted dietary lysine to promote cecal ecosystem invasion in the presence of an intact microbiota. From these findings, we conclude that virulence factor-induced malabsorption of dietary amino acids in the small intestine changes the nutritional environment of the large intestine to provide S. Typhimurium with resources needed to counter growth inhibition by microbiota-derived SCFAs.

Keywords:  Salmonella; colonization resistance; microbiota; short-chain fatty acids

DOI:  https://doi.org/10.1073/pnas.2417232121
Curr Opin Immunol. 2024 Nov 08. pii: S0952-7915(24)00093-1. [Epub ahead of print]91 102503

Metabolic adaptations of ILC2 and Th2 cells in type 2 immunity.

Anna K Kania, Efthymia Kokkinou, Erika Pearce, Edward Pearce.

Type 2 immune responses play a crucial role in host defense against parasitic infections but can also promote the development of allergies and asthma. This response is orchestrated primarily by group 2 innate lymphoid cells (ILC2) and helper type 2 (Th2) cells, both of which undergo substantial metabolic reprogramming as they transition from resting to activated states. Understanding these metabolic adaptations not only provides insights into the fundamental biology of ILC2 and Th2 cells but also opens up potential therapeutic avenues for the identification of novel metabolic targets that can extend the current treatment regimens for diseases in which type 2 immune responses play pivotal roles. By integrating recent findings, this review underscores the significance of cellular metabolism in orchestrating immune functions and highlights future directions for research in this evolving field.

DOI: https://doi.org/10.1016/j.coi.2024.102503
Nat Commun. 2024 Nov 13. 15(1): 9835

Post-translational toxin modification by lactate controls Staphylococcus aureus virulence.

Yanan Wang, Yanfeng Liu, Guoxiu Xiang, Ying Jian, Ziyu Yang, Tianchi Chen, Xiaowei Ma, Na Zhao, Yingxin Dai, Yan Lv, Hua Wang, Lei He, Bisheng Shi, Qian Liu, Yao Liu, Michael Otto, Min Li.

Diverse post-translational modifications have been shown to play important roles in regulating protein function in eukaryotes. By contrast, the roles of post-translational modifications in bacteria are not so well understood, particularly as they relate to pathogenesis. Here, we demonstrate post-translational protein modification by covalent addition of lactate to lysine residues (lactylation) in the human pathogen Staphylococcus aureus. Lactylation is dependent on lactate concentration and specifically affects alpha-toxin, in which a single lactylated lysine is required for full activity and virulence in infection models. Given that lactate levels typically increase during infection, our results suggest that the pathogen can use protein lactylation as a mechanism to increase toxin-mediated virulence during infection.

DOI: https://doi.org/10.1038/s41467-024-53979-8
J Biol Chem. 2024 Nov 05. pii: S0021-9258(24)02476-1. [Epub ahead of print] 107974

Elevated free cholesterol levels due to impaired reverse cholesterol transport are a risk factor for polymicrobial sepsis in mice.

Qian Wang, Ling Guo, Dan Hao, Misa Ito, Chieko Mineo, Philip W Shaul, Xiang-An Li.

  Dysregulated lipid metabolism is commonly observed in septic patients, but how it contributes to sepsis remains largely unknown. Reverse cholesterol transport (RCT) is crucial for regulating cholesterol metabolism in circulation. During RCT, high-density lipoprotein (HDL) collects cholesterol from peripheral tissues and transports it to the liver's scavenger receptor BI (SR-BI), where SR-BI mediates the uptake of cholesteryl esters from HDL for excretion via bile. In this study, we utilized AlbCreSR-BIfl/fl mice, a model with impaired RCT, to investigate the impact of RCT on sepsis. We found that AlbCreSR-BIfl/fl mice were significantly more susceptible to cecal ligation and puncture (CLP)-induced polymicrobial sepsis, with a survival rate of 14.3% compared to 80% in SR-BIfl/fl littermates. Mechanistically, sepsis disrupted cholesterol metabolism, causing a 4.8-fold increase in free cholesterol (FC) levels and a 4-fold increase in the FC/cholesteryl ester (CE) ratio in AlbCreSR-BIfl/fl mice compared to SR-BIfl/fl littermates. This disruption led to hemolysis and death. Notably, administering the cholesterol-lowering drug probucol normalized FC levels and the FC/CE ratio, and significantly improved survival in CLP-AlbCreSR-BIfl/fl mice. However, probucol treatment reduced survival in CLP-LDLR-/- mice, which had elevated CE levels with a low FC/CE ratio. These results highlight that elevated FC levels with high FC/CE ratio are a risk factor for sepsis. Therefore, selectively targeting elevated FC levels and FC/CE ratio could be a promising therapeutic strategy for managing sepsis.

Keywords:  SR-BI; Scarb1; cholesterol; hemolysis; reverse cholesterol transport; sepsis

DOI:  https://doi.org/10.1016/j.jbc.2024.107974
Nutrients. 2024 Oct 27. pii: 3655. [Epub ahead of print]16(21):

IL-33 Induces a Switch in Intestinal Metabolites Revealing the Tryptophan Pathway as a Target for Inducing Allograft Survival.

Camila Pinto, Tomás Carrasco-Loncharic, Eduardo González-Mienert, Javiera de Solminihac, Felipe Gálvez-Jirón, Federico Cifuentes, Karina Pino-Lagos.

  BACKGROUND: IL-33, a pleiotropic cytokine, has been associated with a plethora of immune-related processes, both inflammatory and anti-inflammatory. T regulatory (Treg) cells, the main leukocyte population involved in immune tolerance, can be induced by the administration of IL-33, the local microbiota, and its metabolites. Here, we demonstrate that IL-33 drastically induces the production of intestinal metabolites involved on tryptophan (Trp) metabolism.METHODS: naïve mice were treated with IL-33 for 4 days and leukocyte populations were analyzed by flow cytometry, and feces were processed for microbiota and intestinal metabolites studies. Using a murine skin transplantation model, the effect of Kynurenic acid (KA) on allograft survival was tested.
RESULTS: Under homeostatic conditions, animals treated with IL-33 showed an increment in Treg cell frequencies. Intestinal bacterial abundance analysis indicates that IL-33 provokes dysbiosis, demonstrated by a reduction in Enterobacteria and an increment in Lactobacillus genera. Furthermore, metabolomics analysis showed a dramatic IL-33 effect on the abundance of intestinal metabolites related to amino acid synthesis pathways, highlighting molecules linked to Trp metabolism, such as kynurenic acid (KA), 5-Hydroxyindoleacetic acid (5-HIAA), and 6-Hydroxynicotinic acid (6-HNA), which was supported by an enhanced expression of Ido and Kat mRNA in MLN cells, which are two enzymes involved on KA synthesis. Interestingly, animals receiving KA in drinking water and subjected to skin transplantation showed allograft acceptance, which is associated with an increment in Treg cell frequencies.
CONCLUSIONS: Our study reveals a new property for IL-33 as a modulator of the intestinal microbiota and metabolites, especially those involved with Trp metabolism. In addition, we demonstrate that KA favors Tregs in vivo, positively affecting skin transplantation survival.

Keywords:  IL-33; T regulatory cells; microbiota; tolerance; transplantation; tryptophan

DOI:  https://doi.org/10.3390/nu16213655
PLoS Genet. 2024 Nov 11. 20(11): e1011476

A naturally occurring mitochondrial genome variant confers broad protection from infection in Drosophila.

Tiina S Salminen, Laura Vesala, Yuliya Basikhina, Megan Kutzer, Tea Tuomela, Ryan Lucas, Katy Monteith, Arun Prakash, Tilman Tietz, Pedro F Vale.

The role of mitochondria in immunity is increasingly recognized, but it is unclear how variation in mitochondrial DNA (mtDNA) contributes to variable infection outcomes. To quantify the effect of mtDNA variation on humoral and cell-mediated innate immune responses, we utilized a panel of fruit fly Drosophila melanogaster cytoplasmic hybrids (cybrids), where unique mtDNAs (mitotypes) were introgressed into a controlled isogenic nuclear background. We observed substantial heterogeneity in infection outcomes within the cybrid panel upon bacterial, viral and parasitoid infections, driven by the mitotype. One of the mitotypes, mtKSA2 protected against bacterial, parasitoid, and to a lesser extent, viral infections. Enhanced survival was not a result of improved bacterial clearance, suggesting mtKSA2 confers increased disease tolerance. Transcriptome sequencing showed that the mtKSA2 mitotype had an upregulation of genes related to mitochondrial respiration and phagocytosis in uninfected flies. Upon infection, mtKSA2 flies exhibited infection type and duration specific transcriptomic changes. Furthermore, uninfected mtKSA2 larvae showed immune activation of hemocytes (immune cells), increased hemocyte numbers and ROS production, and enhanced encapsulation response against parasitoid wasp eggs and larvae. Our results show that mtDNA variation acts as an immunomodulatory factor in both humoral and cell-mediated innate immunity and that specific mitotypes can provide broad protection against infections.

DOI: https://doi.org/10.1371/journal.pgen.1011476
Sci Rep. 2024 11 08. 14(1): 27182

Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.

Lena Wischhof, Amal John Mathew, Lorenzo Bonaguro, Marc Beyer, Dan Ehninger, Pierluigi Nicotera, Daniele Bano.

  Inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) system can lead to metabolic disorders and neurodegenerative diseases. In primary mitochondrial disorders, reactive astrocytes often accompany neuronal degeneration and may contribute to neurotoxic inflammatory cascades that elicit brain lesions. The influence of mitochondria to astrocyte reactivity as well as the underlying molecular mechanisms remain elusive. Here we report that mitochondrial Complex I dysfunction promotes neural progenitor cell differentiation into astrocytes that are more responsive to neuroinflammatory stimuli. We show that the SWItch/Sucrose Non-Fermentable (SWI/SNF/BAF) chromatin remodeling complex takes part in the epigenetic regulation of astrocyte responsiveness, since its pharmacological inhibition abrogates the expression of inflammatory genes. Furthermore, we demonstrate that Complex I deficient human iPSC-derived astrocytes negatively influence neuronal physiology upon cytokine stimulation. Together, our data describe the SWI/SNF/BAF complex as a sensor of altered mitochondrial OXPHOS and a downstream epigenetic regulator of astrocyte-mediated neuroinflammation.

Keywords:  ATP-dependent chromatin remodeling SWI/SNF/BAF complex; Mitochondria; Reactive astrocytes

DOI:  https://doi.org/10.1038/s41598-024-78434-y