bims-imicid 2024-11-10 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–11–10
twenty-six papers selected by
Dylan Ryan, University of Cambridge

Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia.
Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.
Immunometabolism: signaling pathways, homeostasis, and therapeutic targets.
Mitochondrial mechanisms in Treg cell regulation: Implications for immunotherapy and disease treatment.
Food for thought: Nutrient metabolism controlling early T cell development.
Influenza A virus-induced glycolysis facilitates virus replication by activating ROS/HIF-1α pathway.
Immunometabolic Effect of Nitric Oxide on Human Macrophages Challenged With the SARS-CoV2-Induced Cytokine Storm. A Fluxomic Approach.
Obesity uncovers presence of inflammatory lung macrophage subsets with adipose tissue transcriptomic signature in influenza virus infection.
Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells.
Coenzyme A fueling with pantethine limits autoreactive T cell pathogenicity in experimental neuroinflammation.
Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes.
Glutamine modulates neutrophil recruitment and effector functions during sterile inflammation.
Microbiota-derived short-chain fatty acids functions in the biology of B lymphocytes: From differentiation to antibody formation.
COQ6 defies immune and metabolic expectations.
Toxoplasma gondii Sustains Survival by Regulating Cholesterol Biosynthesis and Uptake via SREBP2 Activation.
Insulin Mediates Lipopolysaccharide-Induced Inflammatory Responses and Oxidative Stress in BV2 Microglia.
Acute exercise boosts NAD+ metabolism of human peripheral blood mononuclear cells.
Fat keeps metabolism in tune and on time using an inflammatory immune protein.
Applying metabolic control strategies to engineered T cell cancer therapies.
Age-Associated Alterations in the Metabolome of Human Vitreous in Bacterial Endophthalmitis.
Glycolytic activity following anti-CD19 CAR-T cell infusion in non-Hodgkin lymphoma.
AdipoR1 promotes pathogenic Th17 differentiation by regulating mitochondrial function through FUNDC1.
MitoTempo treatment as an approach to cure persistent viral infections?
Metabolic dysfunction-associated steatohepatitis reduces interferon and macrophage liver gene signatures in patients with chronic hepatitis B.
Short-chain fatty acids in viral infection: the underlying mechanisms, opportunities, and challenges.
Single high-fat challenge and trained innate immunity: A randomized controlled cross-over trial.

PLoS Pathog. 2024 Nov 05. 20(11): e1012614

Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia.

Cui Wang, Jun Wen, Zijun Yan, Yujun Zhou, Zhande Gong, Ying Luo, Zhenkui Li, Kang Zheng, Haijun Zhang, Nan Ding, Chuan Wang, Cuiming Zhu, Yimou Wu, Aihua Lei.

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in which neutrophils play a critical role. Immune-responsive gene 1 (IRG1), responsible for itaconate production, has emerged as an important regulator of inflammation and infection, but its role during M. pneumoniae infection remains unknown. Here, we reveal that itaconate is an endogenous pro-inflammatory metabolite during M. pneumoniae infection. Irg1 knockout (KO) mice had lower levels of bacterial burden, lactate dehydrogenase (LDH), and pro-inflammatory cytokines compared with wild-type (WT) controls after M. pneumoniae infection. Neutrophils were the major cells producing itaconate during M. pneumoniae infection in mice. Neutrophil counts were positively correlated with itaconate concentrations in bronchoalveolar lavage fluid (BALF) of patients with severe M. pneumoniae pneumonia. Adoptive transfer of Irg1 KO neutrophils, or administration of β-glucan (an inhibitor of Irg1 expression), significantly attenuated M. pneumoniae pneumonia in mice. Mechanistically, itaconate impaired neutrophil bacterial killing and suppressed neutrophil apoptosis via inhibiting mitochondrial ROS. Moreover, M. pneumoniae induced Irg1 expression by activating NF-κB and STAT1 pathways involving TLR2. Our data thus identify Irg1/itaconate pathway as a potential therapeutic target for the treatment of M. pneumoniae pneumonia.

DOI: https://doi.org/10.1371/journal.ppat.1012614
Am J Respir Cell Mol Biol. 2024 Nov 05.

Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.

Christine L Vigeland, Jordan D Link, Henry S Beggs, Yazan Alwarawrah, Brandie M Ehrmann, Hong Dang, Claire M Doerschuk.

  Changes in metabolic activity are key regulators of macrophage activity. Pro-inflammatory macrophages upregulate glycolysis, which promotes an inflammatory phenotype, whereas pro-repair macrophages rely upon oxidative metabolism and glutaminolysis to support their activity. Work to understand how metabolism regulates macrophage phenotype has been done primarily in macrophage cell lines and bone marrow-derived macrophages (BMDM). Our study sought to understand changes in metabolic activity of murine tissue-resident alveolar macrophages (AM) in response to LPS stimulation and to contrast them to BMDM. These studies also determined the contribution of glutamine metabolism using the glutamine inhibitor, DON. We found that compared to BMDM, AM have higher rates of oxygen consumption and contain a higher concentration of intracellular metabolites involved in fatty acid oxidation. In response to LPS, BMDM but not AM increased rates of glycolysis. Inhibition of glutamine metabolism using DON altered the metabolic activity of AM but not BMDM. Within AM, glutamine inhibition led to increases in intracellular metabolites involved in glycolysis, the TCA cycle, fatty acid oxidation, and amino acid metabolism. Glutamine inhibition also altered the metabolic response to LPS within AM but not BMDM. Our data reveal striking differences in the metabolic activity of AM and BMDM.

Keywords:  glutamine; glycolysis; lipids; macrophage; metabolomics

DOI:  https://doi.org/10.1165/rcmb.2023-0249OC
MedComm (2020). 2024 Nov;5(11): e789

Immunometabolism: signaling pathways, homeostasis, and therapeutic targets.

Rongrong Xu, Xiaobo He, Jia Xu, Ganjun Yu, Yanfeng Wu.

  Immunometabolism plays a central role in sustaining immune system functionality and preserving physiological homeostasis within the organism. During the differentiation and activation, immune cells undergo metabolic reprogramming mediated by complex signaling pathways. Immune cells maintain homeostasis and are influenced by metabolic microenvironmental cues. A series of immunometabolic enzymes modulate immune cell function by metabolizing nutrients and accumulating metabolic products. These enzymes reverse immune cells' differentiation, disrupt intracellular signaling pathways, and regulate immune responses, thereby influencing disease progression. The huge population of immune metabolic enzymes, the ubiquity, and the complexity of metabolic regulation have kept the immune metabolic mechanisms related to many diseases from being discovered, and what has been revealed so far is only the tip of the iceberg. This review comprehensively summarized the immune metabolic enzymes' role in multiple immune cells such as T cells, macrophages, natural killer cells, and dendritic cells. By classifying and dissecting the immunometabolism mechanisms and the implications in diseases, summarizing and analyzing advancements in research and clinical applications of the inhibitors targeting these enzymes, this review is intended to provide a new perspective concerning immune metabolic enzymes for understanding the immune system, and offer novel insight into future therapeutic interventions.

Keywords:  checkpoint; homeostasis; immune cells; immunometabolic enzymes; immunometabolism

DOI:  https://doi.org/10.1002/mco2.789
Mitochondrion. 2024 Nov 02. pii: S1567-7249(24)00133-8. [Epub ahead of print] 101975

Mitochondrial mechanisms in Treg cell regulation: Implications for immunotherapy and disease treatment.

Xiaozhen Zhao, Junmei Zhang, Caifeng Li, Weiying Kuang, Jianghong Deng, Xiaohua Tan, Chao Li, Shipeng Li.

  Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. Recent advances in immunometabolism have revealed the pivotal role of mitochondrial dynamics and metabolism in shaping Treg functionality. Tregs depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to support their suppressive functions and long-term survival. Mitochondrial processes such as fusion and fission significantly influence Treg activity, with mitochondrial fusion enhancing bioenergetic efficiency and reducing reactive oxygen species (ROS) production, thereby promoting Treg stability. In contrast, excessive mitochondrial fission disrupts ATP synthesis and elevates ROS levels, impairing Treg suppressive capacity. Furthermore, mitochondrial ROS act as critical signaling molecules in Treg regulation, where controlled levels stabilize FoxP3 expression, but excessive ROS leads to mitochondrial dysfunction and immune dysregulation. Mitophagy, as part of mitochondrial quality control, also plays an essential role in preserving Treg function. Understanding the intricate interplay between mitochondrial dynamics and Treg metabolism provides valuable insights for developing novel therapeutic strategies to treat autoimmune disorders and enhance immunotherapy in cancer.

Keywords:  Autoimmune diseases; Fatty acid oxidation (FAO); Mitochondria; Oxidative phosphorylation (OXPHOS); Regulatory T cells (Tregs)

DOI:  https://doi.org/10.1016/j.mito.2024.101975
Bioessays. 2024 Nov 06. e2400179

Food for thought: Nutrient metabolism controlling early T cell development.

Guy Werlen, Tatiana Hernandez, Estela Jacinto.

  T cells develop in the thymus by expressing a diverse repertoire of either αβ- or γδ-T cell receptors (TCR). While many studies have elucidated how TCR signaling and gene expression control T cell ontogeny, the role of nutrient metabolism is just emerging. Here, we discuss how metabolic reprogramming and nutrient availability impact the fate of developing thymic T cells. We focus on how the PI3K/mTOR signaling mediates various extracellular inputs and how this signaling pathway controls metabolic rewiring during highly proliferative and anabolic developmental stages. We highlight the role of the hexosamine biosynthetic pathway that generates metabolites that are utilized for N- and O-linked glycosylation of proteins and how it impacts TCR expression during T cell ontogeny. We consider the dichotomy in metabolic needs during αβ- versus γδ-T cell lineage commitment as well as how metabolism is also coupled to molecular signaling that controls cell fate.

Keywords:  PI3K/mTOR signaling; glycosylation; hexosamine biosynthesis; mTORC1/mTORC2; nutrient metabolism; thymic T cell development; αβ‐ and γδ‐T cells

DOI:  https://doi.org/10.1002/bies.202400179
Free Radic Biol Med. 2024 Nov 02. pii: S0891-5849(24)01012-8. [Epub ahead of print]

Influenza A virus-induced glycolysis facilitates virus replication by activating ROS/HIF-1α pathway.

Yijia Zhang, Lifeng Chang, Xin Xin, Yixuan Qiao, Wenna Qiao, Jihui Ping, Jun Xia, Juan Su.

  As a highly contagious acute respiratory disease, influenza A virus (A/WSN/1933) poses a huge threat to human health and public health. influenza A virus proliferation relies on glucose metabolism in host cells, yet the effects of influenza A virus on glucose metabolism and the underlying molecular mechanisms remain unclear. Here, we created models of WSN virus-infected mice and A549 cells, along with analyzing metabolomics and transcriptomics data, to investigate how WSN virus infection affects host cell glucose metabolism and specific mechanisms. Analysis of metabolites and gene expression showed that WSN virus infection triggers glycolysis in A549 cells, with notable upregulation of hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), hypoxia-inducible factor-1 alpha (HIF-1α), and elevated lactate levels. Additionally, it leads to mitochondrial impairment and heightened reactive oxygen species (ROS) generation. Elevated levels of glucose may enhance the replication of WSN virus, whereas inhibitors of glycolysis can reduce it. Enhancement of HIF-1α activation facilitated replication of WSN virus through stimulation of lactate synthesis, with the primary influence of glycolysis on WSN virus replication being mediated by ROS/HIF-1α signaling. Mice given HIF-1α inhibitor PTX-478 or glycolysis inhibitor 2-Deoxyglucose (2-DG) exhibited reduced lactate levels and decreased WSN virus replication, along with mitigated weight loss and lung damage. In summary, WSN virus-induced glycolysis has been demonstrated to enhance virus replication through the activation of the ROS/HIF-1α pathway, suggesting potential new targets for combating the virus.

Keywords:  HIF-1α; Influenza A virus; ROS; glycolysis; lung; mitochondria

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.304
Adv Healthc Mater. 2024 Nov 06. e2401688

Immunometabolic Effect of Nitric Oxide on Human Macrophages Challenged With the SARS-CoV2-Induced Cytokine Storm. A Fluxomic Approach.

Sergio Sánchez-García, Adrián Povo-Retana, Silvia Marin, Sergio Madurga, Marco Fariñas, Nuria Aleixandre, Antonio Castrillo, Juan V de la Rosa, Carlota Alvarez-Lucena, Rodrigo Landauro-Vera, Patricia Prieto, Marta Cascante, Lisardo Boscá.

  The cytokine storm associated with SARS-CoV-2 infection is one of the most distinctive pathological signatures in COVID-19 patients. Macrophages respond to this pro-inflammatory challenge by reprogramming their functional and metabolic phenotypes. Interestingly, human macrophages fail to express the inducible form of the NO synthase (NOS2) in response to pro-inflammatory activation and, therefore, NO is not synthesized by these cells. The contribution of exogenously added NO, via a chemical NO-donor, on the immunometabolic changes associated with the cytokine storm is investigated. By using metabolic, transcriptomic, and functional assays the effect of NO in human macrophages is evaluated and found specific responses. Moreover, through integrative fluxomic analysis, pathways modified by NO that contribute to the expression of a particular phenotype in human macrophages are identified, which includes a decrease in mitochondrial respiration and TCA with a slight increase in the glycolytic flux. A significant ROS increase and preserved cell viability are observed in the presence of NO, which may ease the inflammatory response and host defense. Also, NO reverses the cytokine storm-induced itaconate accumulation. These changes offer additional clues to understanding the potential crosstalk between NO and the COVID-19 cytokine storm-dependent signaling pathways.

Keywords:  COVID‐19; ROS; immunometabolism; macrophage; nitric oxide

DOI:  https://doi.org/10.1002/adhm.202401688
J Infect Dis. 2024 Nov 04. pii: jiae535. [Epub ahead of print]

Obesity uncovers presence of inflammatory lung macrophage subsets with adipose tissue transcriptomic signature in influenza virus infection.

Pablo C Alarcon, Cassidy J Ulanowicz, Michelle S M A Damen, John Eom, Keisuke Sawada, Hak Chung, Tara Alahakoon, Jarren R Oates, Jennifer L Wayland, Traci E Stankiewicz, Maria E Moreno-Fernandez, William J Zacharias, Nathan Salomonis, Senad Divanovic.

  Obesity is a risk factor for increased lung damage and disease severity during influenza virus infection. White adipose tissue (WAT) inflammation is a key driver of disease pathogenesis in obesity. Whether and how obesity modifies lung and WAT immune cell character and function in obesity to amplify influenza disease severity remains unknown. We show that obesity establishes a proinflammatory transcriptome in lung immune cells that is further augmented upon influenza virus infection. Unexpectedly, we also show that influenza virus infection induces expression of inflammatory genes in visceral WAT and modifies WAT immune cell milieu in obesity. Notably, a decrease in WAT macrophage (ATM) populations inversely correlates to increase in infiltrating lung macrophage numbers in obese influenza virus-infected mice. Comparison of both lung and WAT immune cell transcriptional landscapes uncovers a presence of a macrophage subset in the lungs whose transcriptomic signatures matched those of an inflammatory ATM subset preferentially found in obese mice. Adoptive transfer of ATMs from obese mice into lean influenza-virus infected mice promotes host immune cell infiltration to the lungs. Together, our novel findings provide evidence of immune cell transcriptome and character changes in the lungs and WAT of influenza virus infected obese, but not lean, mice and suggest that visceral ATMs may contribute to the overall inflammatory milieu in this setting.

Keywords:  Influenza; Macrophage; Obesity

DOI:  https://doi.org/10.1093/infdis/jiae535
Nat Commun. 2024 Nov 01. 15(1): 9464

Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells.

Siwakorn Punyawatthananukool, Ryuma Matsuura, Thamrong Wongchang, Nao Katsurada, Tatsuaki Tsuruyama, Masaki Tajima, Yutaka Enomoto, Toshio Kitamura, Masahiro Kawashima, Masakazu Toi, Koji Yamanoi, Junzo Hamanishi, Shigeo Hisamori, Kazutaka Obama, Varodom Charoensawan, Dean Thumkeo, Shuh Narumiya.

While prostaglandin E2 (PGE2) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by comparative single-cell RNA sequencing of immune cells infiltrating human cancers and syngeneic tumors in female mice. PGE receptors EP4 and EP2 are expressed in lymphocytes and myeloid cells, and their expression is associated with the downregulation of oxidative phosphorylation (OXPHOS) and MYC targets, glycolysis and ribosomal proteins (RPs). Mechanistically, CD8+ T cells express EP4 and EP2 upon TCR activation, and PGE2 blocks IL-2-STAT5 signaling by downregulating Il2ra, which downregulates c-Myc and PGC-1 to decrease OXPHOS, glycolysis, and RPs, impairing migration, expansion, survival, and antitumor activity. Similarly, EP4 and EP2 are induced upon macrophage activation, and PGE2 downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE2-EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells.

DOI: https://doi.org/10.1038/s41467-024-53706-3
J Neuroinflammation. 2024 Nov 05. 21(1): 287

Coenzyme A fueling with pantethine limits autoreactive T cell pathogenicity in experimental neuroinflammation.

Stefano Angiari, Tommaso Carlucci, Simona L Budui, Simone D Bach, Silvia Dusi, Julia Walter, Elena Ellmeier, Alyssa Schnabl, Anika Stracke, Natalie Bordag, Cansu Tafrali, Rina Demjaha, Michael Khalil, Gabriele Angelini, Eleonora Terrabuio, Enrica C Pietronigro, Elena Zenaro, Carlo Laudanna, Barbara Rossi, Gabriela Constantin.

   BACKGROUND: Immune cell metabolism governs the outcome of immune responses and contributes to the development of autoimmunity by controlling lymphocyte pathogenic potential. In this study, we evaluated the metabolic profile of myelin-specific murine encephalitogenic T cells, to identify novel therapeutic targets for autoimmune neuroinflammation.
METHODS: We performed metabolomics analysis on actively-proliferating encephalitogenic T cells to study their overall metabolic profile in comparison to resting T cells. Metabolomics, phosphoproteomics, in vitro functional assays, and in vivo studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), were then implemented to evaluate the effect of metabolic targeting on autoreactive T cell pathogenicity. Finally, we confirmed the translational potential of our targeting approach in human pro-inflammatory T helper cell subsets and in T cells from MS patients.
RESULTS: We found that autoreactive encephalitogenic T cells display an altered coenzyme A (CoA) synthesis pathway, compared to resting T cells. CoA fueling with the CoA precursor pantethine (PTTH) affected essential immune-related processes of myelin-specific T cells, such as cell proliferation, cytokine production, and cell adhesion, both in vitro and in vivo. Accordingly, pre-clinical treatment with PTTH before disease onset inhibited the development of EAE by limiting T cell pro-inflammatory potential in vivo. Importantly, PTTH also significantly ameliorated the disease course when administered after disease onset in a therapeutic setting. Finally, PTTH reduced pro-inflammatory cytokine production by human T helper 1 (Th1) and Th17 cells and by T cells from MS patients, confirming its translational potential.
CONCLUSION: Our data demonstrate that CoA fueling with PTTH in pro-inflammatory and autoreactive T cells may represent a novel therapeutic approach for the treatment of autoimmune neuroinflammation.

Keywords:  Autoreactive T cells; CoA metabolism; EAE; Immunometabolism; Multiple sclerosis; Pantethine

DOI:  https://doi.org/10.1186/s12974-024-03270-w
Cell Metab. 2024 Oct 25. pii: S1550-4131(24)00400-5. [Epub ahead of print]

Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes.

Victor Gray, Weixin Chen, Rachael Julia Yuenyinn Tan, Jia Ming Nickolas Teo, Zhihao Huang, Carol Ho-Yi Fong, Tommy Wing Hang Law, Zi-Wei Ye, Shuofeng Yuan, Xiucong Bao, Ivan Fan-Ngai Hung, Kathryn Choon-Beng Tan, Chi-Ho Lee, Guang Sheng Ling.

  Patients with type 2 diabetes (T2D) are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that patients with T2D and coronavirus disease 2019 (COVID-19) infections, and influenza-infected T2D mice, exhibit defective T helper 1 (Th1) responses, which are an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4+ T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4+ T cells. These abnormalities promote lipid peroxidation (LPO), which drives carbonylation of signal transducer and activator of transcription 4 (STAT4), a crucial Th1-lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates Th1 defects in patients with T2D who have poor glycemic control and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications.

Keywords:  T helper 1 responses; hyperglycemia; lipid peroxidation; protein carbonylation; type 2 diabetes

DOI:  https://doi.org/10.1016/j.cmet.2024.10.004
J Leukoc Biol. 2024 Nov 06. pii: qiae243. [Epub ahead of print]

Glutamine modulates neutrophil recruitment and effector functions during sterile inflammation.

Katharina E M Hellenthal, Katharina Thomas, Nadine Ludwig, Anika Cappenberg, Lena Schemmelmann, Tobias Tekath, Andreas Margraf, Sina Mersmann, Katharina Henke, Jan Rossaint, Alexander Zarbock, Wida Amini.

  During sterile inflammation, tissue damage induces excessive activation and infiltration of neutrophils into tissues, where they critically contribute to organ dysfunction. Tight regulation of neutrophil migration and their effector functions is crucial to prevent overshooting immune responses. Neutrophils utilize more glutamine, the most abundant free α-amino acid in the human blood, than other leukocytes. However, under inflammatory conditions, the body's requirements exceed its ability to produce sufficient amounts of glutamine. This study investigates the impact of glutamine on neutrophil recruitment and their key effector functions. Glutamine treatment effectively reduced neutrophil activation by modulating β2-integrin activity and chemotaxis in vitro. In a murine in vivo model of sterile inflammation induced by renal ischemia-reperfusion injury, glutamine administration significantly attenuated neutrophil recruitment into injured kidneys. Transcriptomic analysis revealed, glutamine induces transcriptomic reprogramming in murine neutrophils, thus improving mitochondrial functionality and glutathione metabolism. Further, glutamine influenced key neutrophil effector functions, leading to decreased production of reactive oxygen species and formation of neutrophil extracellular traps. Mechanistically, we used a transglutaminase 2 inhibitor to identify transglutaminase 2 as a downstream mediator of glutamine effects on neutrophils. In conclusion, our findings suggest that glutamine diminishes activation and recruitment of neutrophils and thus identify glutamine as a potent means to curb overshooting neutrophil responses during sterile inflammation.

Keywords:  NET formation; ROS production; glutamine; neutrophil recruitment

DOI:  https://doi.org/10.1093/jleuko/qiae243
Biomed Pharmacother. 2023 Oct 27. pii: S0753-3322(23)01571-8. [Epub ahead of print]168 115773

Microbiota-derived short-chain fatty acids functions in the biology of B lymphocytes: From differentiation to antibody formation.

Shengming Qu, Yihang Gao, Jingru Ma, Qingzhu Yan.

  Gut bacteria produce various metabolites from dietary fiber, the most abundant of which are short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. Many biological functions, such as host metabolism and the immune system, are regulated by SCFAs because they act on a wide variety of cell types. A growing body of documents has shown that microbiota SCFAs directly regulate B-cell growth, proliferation, and immunoglobulin (Ig) production. As histone deacetylase (HDAC) inhibitors, SCFAs alter gene expression to enhance the expression of critical regulators of B cell growth. In particular, microbiota SCFAs increase the production of acetyl coenzyme A (acetyl-CoA), adenosine triphosphate (ATP), and fatty acids in B cells, which provide the energy and building blocks needed for the growth of plasma B cells. SCFAs play a significant role in promoting the involvement of B cells in host immunity during both homeostatic conditions and disease states. In this context, SCFAs stimulate B-cell activation and promote the differentiation of plasma B cells in response to B cell receptor (BCR)-activating antigens or co-stimulatory receptor ligands. The result may be increased production of IgA. Microbiota SCFAs were found to lower both overall and antigen-specific IgE levels, indicating their potential to mitigate IgE-related allergic reactions, much like their effect on class-switch recombination (CSR) towards IgG and IgA. Therefore, in the future, the therapeutic advantage should be to use specific and diffusible chemicals, such as SCFAs, which show a strong immunoregulatory function of B cells. This review focuses on the role of microbiota-produced SCFAs in regulating B cell development and antibody production, both in health and diseases.

Keywords:  B cells; GPCR; HDAC; Immune modulation; Immunoglobulin; Microbiota; SCFAs

DOI:  https://doi.org/10.1016/j.biopha.2023.115773
Nat Immunol. 2024 Nov 04.

COQ6 defies immune and metabolic expectations.

Samuel E Weinberg, Navdeep S Chandel.

DOI: https://doi.org/10.1038/s41590-024-02005-6
J Lipid Res. 2024 Oct 25. pii: S0022-2275(24)00189-5. [Epub ahead of print] 100684

Toxoplasma gondii Sustains Survival by Regulating Cholesterol Biosynthesis and Uptake via SREBP2 Activation.

Yi-Min Fan, Qing-Qi Zhang, Ming Pan, Zhao-Feng Hou, Lizhi Fu, Xiulong Xu, Si-Yang Huang.

  Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that cannot biosynthesize cholesterol via the mevalonate pathway, it sources this lipid from its host. We discovered that T. gondii infection upregulated the expression of host cholesterol synthesis related genes HMG-CoA reductase(HMGCR), squalene epoxidase (SQLE) and dehydrocholesterol reductase-7 (DHCR7), and increased the uptake pathway gene low-density lipoprotein receptor (LDLR). We found a protein, sterol regulatory element binding protein 2 (SREBP2), which is the key protein regulating the host cholesterol synthesis and uptake during T. gondii infection. T. gondii induced a dose-dependent nuclear translocation of SREBP2. Knockdown SREBP2 reduced T. gondii-induced cholesterol biosynthesis and uptake. Consequently, the parasite's ability to acquire cholesterol was significantly diminished, impairing its invasion, replication, and bradyzoites development. Interfering cholesterol metabolism using AY9944 effectively inhibited T. gondii replication. In summary, SREBP2 played an important role in T. gondii infection in vitro, serving as a potential target for regulating T. gondii-induced cholesterol metabolism, offering insights into the prevention and treatment of toxoplasmosis.

Keywords:  HMGCR; LDLR; SQLE; SREBP2; Toxoplasma gondii; cholesterol

DOI:  https://doi.org/10.1016/j.jlr.2024.100684
J Inflamm Res. 2024 ;17 7993-8008

Insulin Mediates Lipopolysaccharide-Induced Inflammatory Responses and Oxidative Stress in BV2 Microglia.

Chi-Chen Huang, Sheng-Feng Tsai, Shu-Cheng Liu, Mei-Chen Yeh, Hao-Chang Hung, Chu-Wan Lee, Ching-Li Cheng, Pei-Ling Hsu, Yu-Min Kuo.

   Introduction: Insulin, the key hormone for glucose regulation, has garnered attention for its role as an immune modulator. Impaired insulin signaling in the central nervous system is linked to neuroinflammation and neurodegenerative diseases. Microglia, the resident macrophage-like immune cells in the brain, are key regulators of neuroinflammation. However, the mechanisms by which insulin influences microglial immune responses remain relatively unknown.
Methods: This study aimed to assess the effects of post-treatment with insulin [30 minutes after lipopolysaccharide (LPS) exposure] on LPS-induced inflammatory responses in BV2 microglial cells.
Results: Post-treatment with insulin potentiated LPS-induced production of nitric oxide and pro-inflammatory cytokines, such as TNF and IL-6, through activation of the Akt/NF-κB pathway. Insulin also enhanced the ability of BV2 cells to phagocytose bacteria particles and β-amyloid fibrils. Conversely, insulin inhibited activation of NADPH oxidase and reduced intracellular levels of reactive oxygen species in LPS-treated BV2 cells.
Conclusion: Insulin enhances microglial immune competence when challenged by endotoxins but mitigates oxidative stress in these cells.

Keywords:  p47phox; phagocytosis; superoxide dismutase; β-amyloid

DOI:  https://doi.org/10.2147/JIR.S481101
Brain Behav Immun. 2024 Nov 03. pii: S0889-1591(24)00687-1. [Epub ahead of print]

Acute exercise boosts NAD+ metabolism of human peripheral blood mononuclear cells.

David Walzik, Niklas Joisten, Alexander Schenk, Sina Trebing, Kirill Schaaf, Alan J Metcalfe, Polyxeni Spiliopoulou, Johanna Hiefner, Adrian McCann, Carsten Watzl, Per Magne Ueland, Sebastian Gehlert, Anna Worthmann, Charles Brenner, Philipp Zimmer.

  Nicotinamide adenine dinucleotide (NAD+) coenzymes are the central electron carriers in biological energy metabolism. Low NAD+ levels are proposed as a hallmark of ageing and several diseases, which has given rise to therapeutic strategies that aim to tackle these conditions by boosting NAD+ levels. As a lifestyle factor with preventive and therapeutic effects, exercise increases NAD+ levels across various tissues, but so far human trials are mostly focused on skeletal muscle. Given that immune cells are mobilized and redistributed in response to acute exercise, we conducted two complementary trials to test the hypothesis that a single exercise session alters NAD+ metabolism of peripheral blood mononuclear cells (PBMCs). In a randomized crossover trial (DRKS00017686) with 24 young adults (12 female) we show that acute exercise increases gene expression and protein abundance of several key NAD+ metabolism enzymes with high conformity between high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). In a longitudinal exercise trial (DRKS00029105) with 12 young adults (6 female) we confirm these results and reveal that - similar to skeletal muscle - NAD+ salvage is pivotal for PBMCs in response to exercise. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD+ salvage pathway, displayed a pronounced increase in gene expression during exercise, which was accompanied by elevated intracellular NAD+ levels and reduced serum levels of the NAD+ precursor nicotinamide. These results demonstrate that acute exercise triggers NAD+ biosynthesis of human PBMCs with potential implications for immunometabolism, immune effector function, and immunological exercise adaptions.

Keywords:  Exercise; Immune cell; Metabolism; NAD(+); Nicotinamide adenine dinucleotide; PBMC

DOI:  https://doi.org/10.1016/j.bbi.2024.11.004
Nature. 2024 Nov 06.

Fat keeps metabolism in tune and on time using an inflammatory immune protein.



Keywords:  Immunology; Metabolism; Neuroscience

DOI:  https://doi.org/10.1038/d41586-024-03602-z
Metab Eng. 2024 Oct 25. pii: S1096-7176(24)00137-X. [Epub ahead of print]

Applying metabolic control strategies to engineered T cell cancer therapies.

Andrea C Fox, John Blazeck.

  Chimeric antigen receptor (CAR) T cells are an engineered immunotherapy that express synthetic receptors to recognize and kill cancer cells. Despite their success in treating hematologic cancers, CAR T cells have limited efficacy against solid tumors, in part due to the altered immunometabolic profile within the tumor environment, which hinders T cell proliferation, infiltration, and anti-tumor activity. For instance, CAR T cells must compete for essential nutrients within tumors, while resisting the impacts of immunosuppressive metabolic byproducts. In this review, we will describe the altered metabolic features within solid tumors that contribute to immunosuppression of CAR T cells. We'll discuss how overexpression of key metabolic enzymes can enhance the ability of CAR T cells to resist corresponding tumoral metabolic changes or even revert the metabolic profile of a tumor to a less inhibitory state. In addition, metabolic remodeling is intrinsically linked to T cell activity, differentiation, and function, such that metabolic engineering strategies can also promote establishment of more or less efficacious CAR T cell phenotypes. Overall, we will show how applying metabolic engineering strategies holds significant promise to improve CAR T cells for the treatment of solid tumors.

Keywords:  CAR T cell therapies; Cellular engineering; Immunotherapy; Metabolic engineering; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ymben.2024.10.009
Invest Ophthalmol Vis Sci. 2024 Nov 04. 65(13): 6

Age-Associated Alterations in the Metabolome of Human Vitreous in Bacterial Endophthalmitis.

Sreyasi Maiti, Lakshminarayanan Gowtham, Dhanwini Rudraprasad, Vivek P Dave, Joveeta Joseph.

Purpose: Endophthalmitis is a severe inflammatory condition due to intraocular infections that often leads to irreversible blindness. This study aimed to understand the age-dependent metabolic alterations in the vitreous of patients with bacterial endophthalmitis.
Methods: The study included the vitreous metabolome of patients with bacterial endophthalmitis (group 1, n = 15) and uninfected controls (group 2, n = 14), which were further stratified into three groups according to their age: young (0-30 years), middle (31-60 years), and elderly (>60 years). Vitreous samples were subjected to untargeted metabolomic analysis using high-resolution mass spectrometry (HRMS)m and acquired mass spectrometry data were analyzed using MetaboAnalyst 6.0. The altered metabolites with log2FC of ≥2/≤2, P < 0.05, and variable importance in projection > 1 were considered significant.
Results: In a total of 109 endogenous metabolites identified, young and elderly patients with endophthalmitis showed 52 (elevated, 25; reduced, 27; P < 0.05) and 27 (elevated, 19; reduced, 8; P < 0.05) significantly altered metabolites, respectively, compared to their age-matched controls. Additionally, 27 metabolites were differentially expressed in young patients with endophthalmitis compared to the older group. The crucial metabolic pathways dysregulated in the older infected population were de novo purine synthesis and salvage, carnitine, polyamine (spermidine), lipids (prostaglandins), and amino acid (taurine, methionine, histidine) which could possibly be attributed to the increased disease severity and inflammation observed in a clinical setting.
Conclusions: Despite the erratic metabolic changes observed in the younger group infected with endophthalmitis when compared to age-matched controls, dysregulation in the specific pathways such as purine, carnitine, arachidonic acid, and polyamine metabolism could possibly alter the immunological exacerbation observed in the older group.

DOI: https://doi.org/10.1167/iovs.65.13.6
Eur J Clin Invest. 2024 Nov 01. e14342

Glycolytic activity following anti-CD19 CAR-T cell infusion in non-Hodgkin lymphoma.

Nicolas Vallet, Laurianne Drieu Larochelle, Maria-Joao Santiago-Ribeiro, Alban Villate, Martin Eloit, Arnaud Cirée, Laura Zaragoza, Virginie André, Marie Prat-Lepesant, Olivier Hérault, Flavie Arbion, Hélène Blasco, Emmanuel Gyan.

  Energy metabolism of chimeric antigen receptor-T cells (CAR-T) activation in humans remains unexplored. As a glycolytic activity surrogate, we investigated the dynamics of peripheral blood (PB) lactate in the first weeks post-CAR-T infusion. In 17 patients treated with CD28 harbording anti-CD19 CAR-T for relapsed/refractory non-Hodgkin lymphomas, PB lactate levels increased following CAR-T infusion. Elevated lactate levels correlated with longer CAR-T persistence and higher CD8+/CD4+ ratio. Peripheral blood lactate kinetics may reflect immune cells activation and be useful for bedside monitoring.

Keywords:  CAR‐T cells; NHL; T cells; cell therapy; metabolism

DOI:  https://doi.org/10.1111/eci.14342
J Biomed Res. 2024 Nov 25. 1-12

AdipoR1 promotes pathogenic Th17 differentiation by regulating mitochondrial function through FUNDC1.

Hui Wang, Qian Zhang, Yuankai Sun, Wenfeng Tan, Miaojia Zhang.

  Adiponectin receptor 1 ( Adipor1) deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis (AIA) mice. Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic (pTh17) and non-pathogenic (npTh17) cells, with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions. In the current study, we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and that the deletion of Adipor1 in pTh17 cells reduced the mitochondrial function. RNA-sequencing (RNA-seq) demonstrated a significant increase in the expression levels of Fundc1, a gene related to mitochondrial function, in Adipor1-deficient CD4 + T cells. Interference with the Fundc1 expression in Adipor1-deficient CD4 + T cells partially mitigated the effect of Adipor1 deficiency on mitochondrial function and pTh17 differentiation. In conclusion, the current study demonstrated a novel role of AdipoR1 in regulating mitochondrial function via FUNDC1 to promote pTh17 cell differentiation, providing some insights into potential therapeutic targets for autoimmune and inflammatory diseases.

Keywords:  AdipoR1; FUNDC1; mitochondrial function; pTh17

DOI:  https://doi.org/10.7555/JBR.38.20240244
Virology. 2024 Oct 29. pii: S0042-6822(24)00304-0. [Epub ahead of print]600 110280

MitoTempo treatment as an approach to cure persistent viral infections?

Jasmin Mischke, Sebastian Klein, Markus Cornberg, Anke R M Kraft.

  Chronic viral infections are characterized by exhausted virus-specific T cells. Exhaustion is associated with mitochondrial dysfunction, revealing a possible target for treatment. Targeting these metabolic processes may interfere with the exhaustion process of immune cells during infection. It has been shown that the mitochondria-targeted antioxidant MitoTempo could restore hepatitis-B-virus-specific T cells in vitro. Thus, we investigated MitoTempo as a treatment option using the chronic lymphocytic choriomeningitis virus (LCMVcl13) mouse model. MitoTempo treatment of chronically LCMVcl13 infected mice resulted in a transient reduction of LCMV titer. However, no obvious restoration of functional LCMV-specific T cells was observed, beside subtle changes in phenotype of GP33- and NP205-specific T cells. However, these changes did not translate into significantly more functional responses. Our study showed a transient antiviral effect of MitoTempo, but no profound effect on exhausted T cell responses, although further studies are needed to further elucidate the mechanism and use of MitoTempo.

Keywords:  CD8(+) T cells; Chronic viral infection; Immune checkpoint inhibitor therapy; Lymphocytic choriomeningitis virus; MitoTempo; Virus-specific T cells

DOI:  https://doi.org/10.1016/j.virol.2024.110280
J Hepatol. 2024 Oct 26. pii: S0168-8278(24)02653-9. [Epub ahead of print]

Metabolic dysfunction-associated steatohepatitis reduces interferon and macrophage liver gene signatures in patients with chronic hepatitis B.

Zgjim Osmani, Willem Pieter Brouwer, Dwin G B Grashof, Youkyung Lim, Michael Doukas, Harry L A Janssen, Harmen J G van de Werken, Andre Boonstra.

   BACKGROUND & AIMS: Chronic HBV patients with concomitant metabolic dysfunction-associated steatohepatitis (MASH) have been shown to develop more advanced fibrosis faster with more severe liver disease as compared to patients with chronic HBV alone. However, our understanding of the underlying mechanisms is limited. Here we study how MASH co-morbidity impact immune activity in the liver of patients with chronic HBV infection.
METHODS: Bulk RNA sequencing was performed on liver biopsies from patients with only MASH (n=10), only HBeAg-negative chronic HBV (ENEG; n=11), combined MASH/ENEG (n=9) and healthy controls (n=9). Biopsies with no or minimal fibrosis (≤F2) were selected to avoid confounding effects of fibrosis. We compared whole transcriptome data from patients with MASH/ENEG to those with ENEG alone to determine the impact of MASH co-morbidity on chronic hepatitis B.
RESULTS: There is a high degree of overlap of liver gene expression profiles in patients with only ENEG versus those with only MASH compared to healthy controls, suggesting a largely shared mechanism of liver dysfunction and immune activity for these distinct conditions. In patients with ENEG, MASH co-morbidity significantly reduced interferon pathway activity (NES=2.03, p.adj=0.0251), the expression of ISGs (e.g., IFIT2, IFI27, IFITM1, IFI6), and macrophage gene signatures (e.g., MARCO, CD163, CD5L, CD63), when compared to patients with ENEG alone.
CONCLUSIONS: Transcriptomic profiling of the liver suggests that MASH negatively impacts ISGs expression in the liver of patients with ENEG, which may affect antiviral immune pathways, viral replication and inflammatory responses resulting in an increased risk of advanced fibrosis in patients with chronic hepatitis B. Our study provides valuable insights for guiding future research aimed at developing effective, tailored strategies for managing patients with both conditions.
IMPACT AND IMPLICATIONS: In recent decades, obesity and associated health issues have reached epidemic levels, with steatotic liver disease affecting up to 30% of adults in developed countries, and this trend is also observed among chronic hepatitis B patients. Given the high and rising prevalence of steatotic liver disease and its frequent co-occurrence in chronic hepatitis B patients, it is essential to understand how conditions such as metabolic dysfunction-associated steatohepatitis (MASH) impact immune responses in the liver. This study provides unique insights into the impact of MASH on HBV antiviral immune activity in the liver of patients with chronic hepatitis B. The rising number of patients with both conditions affects treatment outcomes and highlights the urgent need for novel, tailored therapeutic strategies. Our study holds significant relevance for guiding future research on developing treatment strategies for patients with both MASH and chronic hepatitis B.

Keywords:  RNA sequencing; chronic hepatitis B; liver biopsies; metabolic dysfunction-associated steatohepatitis

DOI:  https://doi.org/10.1016/j.jhep.2024.10.032
Trends Microbiol. 2024 Nov 05. pii: S0966-842X(24)00261-0. [Epub ahead of print]

Short-chain fatty acids in viral infection: the underlying mechanisms, opportunities, and challenges.

Yee Tsui, Xueqi Wu, Xi Zhang, Ye Peng, Chris Ka Pun Mok, Francis K L Chan, Siew C Ng, Hein Min Tun.

  Viral infections can cause cellular pathway derangements, cell death, and immunopathological responses, leading to host inflammation. Short-chain fatty acids (SCFAs), produced by the microbiota, have emerged as a potential therapeutic for viral infections due to their ability to modulate these processes. However, SCFAs have been reported to have both beneficial and detrimental effects, necessitating a comprehensive understanding of the underlying mechanisms. This review highlights the complex mechanisms underlying SCFAs' effects on viral infection outcomes. We also emphasize the importance of considering how SCFAs' activities may differ under diverse contexts, including but not limited to target cells with different metabolic wiring, different viral causes of infection, the target organism/cell's nutrient availability and/or energy balance, and hosts with varying microbiome compositions.

Keywords:  gut microbiota; immunomodulation; multi-omics; short-chain fatty acids; viral infection

DOI:  https://doi.org/10.1016/j.tim.2024.10.001
iScience. 2024 Nov 15. 27(11): 111103

Single high-fat challenge and trained innate immunity: A randomized controlled cross-over trial.

Julia van Tuijl, Julia I P van Heck, Harsh Bahrar, Wieteke Broeders, Johan Wijma, Yvonne M Ten Have, Martin Giera, Heidi Zweers-van Essen, Laura Rodwell, Leo A B Joosten, Mihai G Netea, Lydia A Afman, Siroon Bekkering, Niels P Riksen.

  Brief exposure of monocytes to atherogenic molecules, such as oxidized lipoproteins, triggers a persistent pro-inflammatory phenotype, named trained immunity. In mice, transient high-fat diet leads to trained immunity, which aggravates atherogenesis. We hypothesized that a single high-fat challenge in humans induces trained immunity. In a randomized controlled cross-over study, 14 healthy individuals received a high-fat or reference shake, and blood was drawn before and after 1, 2, 4, 6, 24, and 72 h. Incubation of donor monocytes with the post-high-fat-shake serum induced trained immunity, regulated via Toll-like receptor 4. This was not mediated via triglyceride-rich lipoproteins, C12, 14, and 16, or metabolic endotoxemia. In vivo, however, the high-fat challenge did not affect monocyte phenotype and function. We conclude that a high-fat challenge leads to alterations in the serum composition that have the potential to induce trained immunity in vitro. However, this does not translate into a (persistent) hyperinflammatory monocyte phenotype in vivo.

Keywords:  Health sciences; Human Physiology; Human metabolism

DOI:  https://doi.org/10.1016/j.isci.2024.111103