bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023‒01‒22
thirty papers selected by
Dylan Ryan
University of Cambridge

  1. Nat Immunol. 2023 Jan 19.
      Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown. Although antibody secretion is considered to be imprinted during B cell differentiation and therefore largely unaffected by environmental changes, a rapid modulation of IgA levels in response to intestinal fluctuations might be beneficial to the host. In the present study, we showed that dietary cholesterol absorption and commensal recognition by duodenal intestinal epithelial cells lead to the production of oxysterols, evolutionarily conserved lipids with immunomodulatory functions. Using conditional cholesterol 25-hydroxylase deleter mouse line we demonstrated that 7α,25-dihydroxycholesterol from epithelial cells is critical to restrain IgA secretion against commensal- and pathogen-derived antigens in the gut. Intestinal plasma cells sense oxysterols via the chemoattractant receptor GPR183 and couple their tissue positioning with IgA secretion. Our findings revealed a new mechanism linking dietary cholesterol and humoral immune responses centered around plasma cell localization for efficient mucosal protection.
  2. Cell Rep. 2023 Jan 18. pii: S2211-1247(23)00022-0. [Epub ahead of print]42(1): 112011
      Systemic metabolites serving as danger-associated molecular patterns play crucial roles in modulating the development, differentiation, and activity of innate immune cells. Yet, it is unclear how innate immune cells detect systemic metabolites for signal transmission. Here, we show that bile acids function as endogenous mitofusin 2 (MFN2) ligands and differentially modulate innate immune response to bacterial infection under cholestatic and physiological conditions. Bile acids at high concentrations promote mitochondrial tethering to the endoplasmic reticulum (ER), leading to calcium overload in the mitochondrion, which activates NLRP3 inflammasome and pyroptosis. By contrast, at physiologically relevant low concentrations, bile acids promote mitochondrial fusion, leading to enhanced oxidative phosphorylation and thereby strengthening infiltrated macrophages mediated phagocytotic clearance of bacteria. These findings support that bile acids, as endogenous activators of MFN2, are vital for tuning innate immune responses against infections, representing a causal link that connects systemic metabolism with mitochondrial dynamics in shaping innate immunity.
    Keywords:  Bile acids; CP: Metabolism; CP: Molecular biology; Infection; Macrophage; Metabolism; Mitochondrion; Mitofusin 2
  3. Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2214484120
      The microbiota performs multiple functions vital to host fitness, including defense against pathogens and adaptation to dietary changes. Yet, how environmental challenges shape microbiota resilience to nutrient fluctuation remains largely unexplored. Here, we show that transient gut infection can optimize host metabolism toward the usage of carbohydrates. Following acute infection and clearance of the pathogen, mice gained more weight as a result of white adipose tissue expansion. Concomitantly, previously infected mice exhibited enhanced carbohydrate (glucose) disposal and insulin sensitivity. This metabolic remodeling depended on alterations to the gut microbiota, with infection-elicited Betaproteobacteria being sufficient to enhance host carbohydrate metabolism. Further, infection-induced metabolic alteration protected mice against stunting in the context of limited nutrient availability. Together, these results propose that alterations to the microbiota imposed by acute infection may enhance host fitness and survival in the face of nutrient restriction, a phenomenon that may be adaptive in settings where both infection burden and food precarity are prevalent.
    Keywords:  Yersinia; carbohydrate; host metabolism; malnutrition; white adipose tissue
  4. Nat Metab. 2023 Jan 19.
      Immediate restriction of iron initiated by the host is a critical process to protect against bacterial infections and has been described in the liver and spleen, but it remains unclear whether this response also entails a humoral mechanism that would enable systemic sequestering of iron upon infection. Here we show that upon bacterial invasion, host macrophages immediately release extracellular vesicles (EVs) that capture circulating iron-containing proteins. Mechanistically, in a sepsis model in female mice, Salmonella enterica subsp. enterica serovar Typhimurium induces endoplasmic reticulum stress in macrophages and activates inositol-requiring enzyme 1α signaling, triggering lysosomal dysfunction and thereby promoting the release of EVs, which bear multiple receptors required for iron uptake. By binding to circulating iron-containing proteins, these EVs prevent bacteria from iron acquisition, which inhibits their growth and ultimately protects against infection and related tissue damage. Our findings reveal a humoral mechanism that can promptly regulate systemic iron metabolism during bacterial infection.
  5. Front Immunol. 2022 ;13 1063221
      Endoplasmic reticulum (ER) stress plays a major role in several inflammatory disorders. ER stress induces the unfolded protein response (UPR), a conserved response broadly associated with innate immunity and cell metabolic function in various scenarios. Brucella abortus, an intracellular pathogen, triggers the UPR via Stimulator of interferon genes (STING), an important regulator of macrophage metabolism during B. abortus infection. However, whether ER stress pathways underlie macrophage metabolic function during B. abortus infection remains to be elucidated. Here, we showed that the UPR sensor inositol-requiring enzyme 1α (IRE1α) is as an important component regulating macrophage immunometabolic function. In B. abortus infection, IRE1α supports the macrophage inflammatory profile, favoring M1-like macrophages. IRE1α drives the macrophage metabolic reprogramming in infected macrophages, contributing to the reduced oxidative phosphorylation and increased glycolysis. This metabolic reprogramming is probably associated with the IRE1α-dependent expression and stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), an important molecule involved in cell metabolism that sustains the inflammatory profile in B. abortus-infected macrophages. Accordingly, we demonstrated that IRE1α favors the generation of mitochondrial reactive oxygen species (mROS) which has been described as an HIF-1α stabilizing factor. Furthermore, in infected macrophages, IRE1α drives the production of nitric oxide and the release of IL-1β. Collectively, these data unravel a key mechanism linking the UPR and the immunometabolic regulation of macrophages in Brucella infection and highlight IRE1α as a central pathway regulating macrophage metabolic function during infectious diseases.
    Keywords:  HIF-1α; IRE1α; UPR; brucella abortus; endoplasmic reticulum stress; immunometabolism
  6. Mucosal Immunol. 2023 Jan 12. pii: S1933-0219(22)01180-1. [Epub ahead of print]
      The concept of immunometabolism has emerged recently whereby repolarizing of inflammatory immune cells towards anti-inflammatory profiles by manipulating cellular metabolism represents a new potential therapeutic approach in controlling inflammation.Metabolic pathways in immune cells are tightly regulated to maintain immune homeostasis and appropriate functional specificity. As effector and regulatory immune cell populations have different metabolic requirements, this allows for cellular selectivity when regulating immune responses based on metabolic pathways. Gut microbes have a major role in modulating immune cell metabolic profiles and functional responses through extensive interactions involving metabolic products and crosstalk between gut microbes, intestinal epithelial cells, and mucosal immune cells. Developing strategies to target metabolic pathways in mucosal immune cells through modulation of gut microbial metabolism has the potential for new therapeutic approaches for human autoimmune and inflammatory diseases, such as inflammatory bowel disease. This review will give an overview of the relationship between metabolic reprogramming and immune responses, how microbial metabolites influence these interactions, and how these pathways could be harnessed in the treatment of inflammatory bowel disease.
    Keywords:  immunometabolism; inflammatory bowel disease; microbiome
  7. Am J Physiol Cell Physiol. 2023 Jan 16.
      Macrophages are crucial effector cells of the innate immune system and have important roles in the initiation and resolution of inflammation as well as in tissue homeostasis. In order to fulfill these diverse roles, macrophages exhibit metabolic flexibility to quickly adapt to the needs of the effector functions required, as well as to the microenvironment. This metabolic flexibility is exemplified by pro-inflammatory macrophages, which upregulate glycolysis to both initiate and sustain the process of inflammation. Upregulation of glycolysis does not only represent a fast means of ATP generation. It also fuels glycolytic side pathways that are crucial for an effective inflammatory response by influencing the cell's redox balance as well as by providing building blocks and substrates for epigenetic reprogramming. The aim of this short review is to explore how three of these pathways - the pentose phosphate pathway, the glycerol phosphate shuttle, and the serine synthesis pathway - help macrophages sustain their pro-inflammatory phenotype and functions.
    Keywords:  glycolysis; immunometabolism; macrophage
  8. Immunometabolism (Cobham). 2023 Jan;5(1): e00014
      Challenges regarding successful immunotherapy are associated with the heterogeneity of tumors and the complex interactions within the surrounding tumor microenvironment (TME), particularly those between immune and tumor cells. Of interest, T cells receive a myriad of environmental signals to elicit differentiation to effector subtypes, which is accompanied by metabolic reprogramming needed to satisfy the high energy and biosynthetic demands of their activated state. However, T cells are subjected to immunosuppressive signals and areas of oxygen and nutrient depletion in the TME, which causes T-cell exhaustion and helps tumor cells escape immune detection. The cytosolic and mitochondrial branched chain amino transferases, BCATc and BCATm, respectively, are responsible for the first step of the branched chain amino acid (BCAA) degradation, of which, metabolites are shunted into various metabolic processes. In recent years, BCAT isoenzymes have been investigated for their role in a variety of cancers found throughout the body; however, a gap of knowledge exists regarding the role BCAT isoenzymes play within immune cells of the TME. The aim of this review is to summarize recent findings about BCAAs and their catabolism at the BCAT step during T-cell metabolic reprogramming and to discuss the BCAT putative role in the anti-tumor immunity of T cells. Not only does this review acknowledges gaps pertaining to BCAA metabolism in the TME but it also identifies the practical application of BCAA metabolism in T cells in response to cancer and spotlights a potential target for pharmacological intervention.
    Keywords:  BCAA; BCATc; BCATm; TME; immunotherapy; leucine
  9. EMBO Rep. 2023 Jan 18. e55286
      An increasing amount of evidence emphasizes the role of metabolic reprogramming in immune cells to fight infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of equilibrative nucleoside transporter 3 (ENT3, encoded by solute carrier family 29 member 3, Slc29a3) is part of the innate immune response, which is rapidly upregulated upon pathogen invasion. The transcription of Slc29a3 is directly regulated by type I interferon-induced signaling, demonstrating that this metabolite transporter is an interferon-stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS-CoV-2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of Slc29a3 expression is sufficient to significantly decrease viral replication in vitro and in vivo. Our study reveals that ENT3 is a pro-viral ISG co-opted by some viruses to gain a survival advantage.
    Keywords:  equilibrative nucleoside transporter; interferon-stimulated gene; macrophage; metabolite transporter; viral replication
  10. Sci Bull (Beijing). 2021 Sep 15. pii: S2095-9273(21)00123-7. [Epub ahead of print]66(17): 1806-1816
      The essential trace element iron regulates a wide range of biological processes in virtually all living organisms. Because both iron deficiency and iron overload can lead to various pathological conditions, iron homeostasis is tightly regulated, and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease. In recent years, significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system. Here, we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease, processes in which both the host and the pathogen compete for iron. We also discuss the evidence and implications that immune cells such as macrophages, T cells, and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions, in which iron serves as a co-factor in toll-like receptor 4 (TLR4) signaling, mitochondrial respiration, posttranslational regulation, and epigenetic modification. In addition, we discuss the therapeutic implications of targeting ferroptosis, iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection, controlling inflammation, and improving the efficacy of immunotherapy.
    Keywords:  Anemia of inflammation; Ferroptosis; Inflammatory response; Iron homeostasis; Iron overload
  11. Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2212813120
      The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1β production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic Escherichia coli (UPEC). HDAC7-mediated PPP engagement via 6-phosphogluconate dehydrogenase (6PGD) generates NADPH for antimicrobial ROS production, as well as D-ribulose-5-phosphate (RL5P) that both synergizes with ROS for UPEC killing and suppresses selective inflammatory responses. This dual functionality of the HDAC7-6PGD-RL5P axis prioritizes responses to proximal threats. Our findings thus reveal that the PPP metabolite RL5P has both antimicrobial and immunomodulatory activities and that engagement of enzymes in catabolic versus anabolic metabolic pathways triages responses to different types of danger for generation of inflammatory versus antimicrobial responses, respectively.
    Keywords:  immunometabolism; inflammation; macrophages; pentose phosphate pathway; uropathogenic Escherichia coli
  12. Elife. 2023 Jan 17. pii: e83075. [Epub ahead of print]12
      Analogues of the hepatokine FGF21 are in clinical development for type 2 diabetes and nonalcoholic steatohepatitis (NASH) treatment. Although their glucose-lowering and insulin-sensitizing effects have been largely unraveled, the mechanisms by which they alleviate liver injury have only been scarcely addressed. Here, we aimed to unveil the mechanisms underlying the protective effects of FGF21 on NASH using APOE*3-Leiden.CETP mice, a well-established model for human-like metabolic diseases. Liver-specific FGF21 overexpression was achieved in mice, followed by administration of a high-fat high-cholesterol diet for 23 weeks. FGF21 prevented hepatic lipotoxicity, accompanied by activation of thermogenic tissues and attenuation of adipose tissue inflammation, improvement of hyperglycemia and hypertriglyceridemia, and upregulation of hepatic programs involved in fatty acid oxidation and cholesterol removal. Furthermore, FGF21 inhibited hepatic inflammation, as evidenced by reduced Kupffer cell (KC) activation, diminished monocyte infiltration and lowered accumulation of monocyte-derived macrophages. Moreover, FGF21 decreased lipid- and scar-associated macrophages, which correlated with less hepatic fibrosis as demonstrated by reduced collagen accumulation. Collectively, hepatic FGF21 overexpression limits hepatic lipotoxicity, inflammation and fibrogenesis. Mechanistically, FGF21 blocks hepatic lipid influx and accumulation through combined endocrine and autocrine signaling, respectively, which prevents KC activation and lowers the presence of lipid- and scar-associated macrophages to inhibit fibrogenesis.
    Keywords:  immunology; inflammation; medicine; mouse
  13. J Steroid Biochem Mol Biol. 2023 Jan 13. pii: S0960-0760(23)00006-7. [Epub ahead of print]228 106251
      1,25-Dihydroxyvitamin D (1,25(OH)2D3) has immunomodulatory activity and its deficiency correlates with rheumatoid arthritis (RA) incidence. Whether 1,25(OH)2D3 modulates macrophage activation or protects against RA remains unclear. We demonstrate that 1,25(OH)2D3 suppresses M1 macrophage polarization and CD80, IL-6, CXCL10, IFIT1, IFI44, and double-stranded RNA-dependent protein kinase R (PKR) expression in the macrophages of RA patients. In phorbol 12-myristate 13-acetate-induced THP-1 cells, 1,25(OH)2D3 upregulates fructose-1,6-bisphosphatase 1 (FBP1) expression through direct promoter interaction. FBP1 interacts with PKR and promotes PKR ubiquitination degradation. SiR-FBP1 transfection impairs 1,25(OH)2D3 action and suppresses IL-6, CXCL10, IFIT1, IFI27, and IFI44 expression in macrophages, whereas siR-PKR transfection impairs siR-FBP1 activity in 1,25(OH)2D3-treated macrophages. 1,25(OH)2D3 treatment ameliorates the clinical signs of arthritis in tumor necrosis factor-transgenic mice, inhibits M1 polarization and marker expression, and promotes FBP1 expression in mononuclear cells isolated from swollen joints; thus, 1,25(OH)2D3 suppresses M1 macrophage activation through FBP1/PKR and ameliorates arthritis by restoring the macrophage subtype.
    Keywords:  1,25(OH)(2)D(3); Arthritis; FBP1; Macrophages
  14. Life Sci. 2023 Jan 16. pii: S0024-3205(23)00034-6. [Epub ahead of print] 121400
      AIMS: Activation of specific innate immune receptors has been characterized to modulate nutrient metabolism in individual metabolic tissue directly or indirectly via secretory molecules. Activation of the nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in adipocytes has been reported to induce lipolysis linked with insulin resistance and inflammatory response. These cues are positioned to modulate metabolic action in distal organs through paracrine/endocrine signaling. Here, we assessed the role of NOD1-mediated lipolysis and inflammatory response in adipocytes to affect lipid metabolism in hepatocytes.MAIN METHODS: Human hepatoma cells (HepG2) were exposed to conditioned medium obtained from 3 T3-L1 adipocytes pretreated with NOD1 ligand (iE-DAP) and the effects on lipid accumulation, inflammation and insulin response were assessed. Activation of mechanisms leading to hepatic lipid accumulation was investigated by gene expression analysis.
    KEY FINDINGS: The conditioned medium from NOD1-activated 3 T3-L1 adipocytes (CM-DAP) induced lipid accumulation in HepG2 cells, driven by both lipolysis and inflammatory responses. The CM-DAP-induced lipid accumulation was independent to de novo lipogenesis and resulted from the enhanced transport of fatty acids inside and consequent increase in rate of triglycerides synthesis in hepatocytes. Moreover, CM-DAP-induced lipid accumulation instigated the expression of the markers of fatty acid oxidation and VLDL assembly for the export of triglycerides from hepatocyte. Furthermore, CM-DAP-induced lipid accumulation was associated with induction of inflammatory response and impairment of insulin signaling in HepG2 cells.
    SIGNIFICANCE: Beyond showing liver-specific mechanisms to adipocytes-derived factors, our findings support the involvement of adipose tissue as a mediator in NOD1-mediated biological responses to modulate hepatic metabolism.
    Keywords:  Hepatic steatosis; Inflammation; Insulin resistance; Lipogenesis; NOD1
  15. Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2208924120
      Nitro-fatty acids (NO2-FAs) are unsaturated fatty acid nitration products that exhibit anti-inflammatory actions in experimental mouse models of autoimmune and allergic diseases. These electrophilic molecules interfere with intracellular signaling pathways by reversible post-translational modification of nucleophilic amino-acid residues. Several regulatory proteins have been identified as targets of NO2-FAs, modifying their activity and promoting gene expression changes that result in anti-inflammatory effects. Herein, we report the effects of nitro-oleic acid (NO2-OA) on pro-inflammatory T cell functions, showing that 9- and 10-NOA, but not their oleic acid precursor, decrease T cell proliferation, expression of activation markers CD25 and CD71 on the plasma membrane, and IL-2, IL-4, and IFN-γ cytokine gene expressions. Moreover, we have found that NO2-OA inhibits the transcriptional activity of nuclear factor of activated T cells (NFAT) and that this inhibition takes place through the regulation of the phosphatase activity of calcineurin (CaN), hindering NFAT dephosphorylation, and nuclear translocation in activated T cells. Finally, using mass spectrometry-based approaches, we have found that NO2-OA nitroalkylates CaNA on four Cys (Cys129, 228, 266, and 372), of which only nitroalkylation on Cys372 was of importance for the regulation of CaN phosphatase activity in cells, disturbing functional CaNA/CaNB heterodimer formation. These results provide evidence for an additional mechanism by which NO2-FAs exert their anti-inflammatory actions, pointing to their potential as therapeutic bioactive lipids for the modulation of harmful T cell-mediated immune responses.
    Keywords:  NFAT; T cells; calcineurin; inflammation; nitro-fatty acids
  16. Curr Issues Mol Biol. 2023 Jan 16. 45(1): 765-781
      Neuroinflammation is one of the common features in most neurological diseases including multiple sclerosis (MScl) and neurodegenerative diseases such as Alzheimer's disease (AD). It is associated with local brain inflammation, microglial activation, and infiltration of peripheral immune cells into cerebrospinal fluid (CSF) and the central nervous system (CNS). It has been shown that the diversity of phenotypic changes in monocytes in CSF relates to neuroinflammation. It remains to be investigated whether these phenotypic changes are associated with functional or metabolic alteration, which may give a hint to their function or changes in cell states, e.g., cell activation. In this article, we investigate whether major metabolic pathways of blood monocytes alter after exposure to CSF of healthy individuals or patients with AD or MScl. Our findings show a significant alteration of the metabolism of monocytes treated with CSF from patients and healthy donors, including higher production of citric acid and glutamine, suggesting a more active glycolysis and tricarboxylic acid (TCA) cycle and reduced production of glycine and serine. These alterations suggest metabolic reprogramming of monocytes, possibly related to the change of compartment (from blood to CSF) and/or disease-related. Moreover, the levels of serine differ between AD and MScl, suggesting different phenotypic alterations between diseases.
    Keywords:  Alzheimer; cerebrospinal fluid; glycolysis; metabolism; metabolites; monocytes; multiple sclerosis; neuroinflammation; tricarboxylic acid cycle
  17. Clin Immunol. 2023 Jan 13. pii: S1521-6616(23)00009-8. [Epub ahead of print]247 109230
      BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event resulting from immunotherapy in patients with malignant tumors. However, the pathogenesis of CIP remains poorly understood.METHODS: We collected bronchoalveolar lavage fluid (BALF) from cohorts of patients with CIP, new-onset lung cancer (LC), and idiopathic pulmonary fibrosis (IPF). Non-targeted metabolomics analysis was conducted to analyze metabolic signatures. Flow cytometry was used to evaluate immune cell subsets.
    RESULTS: Lymphocytes were predominant in the BALF of patients with CIP. A total of 903 metabolites were identified, among which lipid compounds were the most abundant. In a comparison between patients with CIP and LC, enrichment analysis of the altered metabolites showed suppressed amino sugar metabolism, and spermidine and spermine biosynthesis in the CIP group. Metabolism of alpha linolenic acid, linoleic acid, and their fatty acid derivatives was enriched in the CIP group relative to the IPF group. The twelve metabolites found to be enriched in the CIP group were positively correlated with the proportion of CD8+ T cells. One cluster of BALF metabolites, 57.14% of which were lipid molecules, was inversely correlated with the proportion of natural killer cells.
    CONCLUSIONS: In this study, the metabolomic landscape of BALF in patients with CIP was determined. We elucidated suppressed tumor metabolic signatures, enhanced pulmonary inflammatory signaling, and the characteristics of responsible immune cells, which helps to understand the pathogenesis of CIP.
    Keywords:  Bronchoalveolar lavage fluid; Checkpoint inhibitor pneumonitis; Flow cytometry; Idiopathic pulmonary fibrosis; Lung cancer; Metabolomics analysis
  18. J Immunol. 2023 Jan 16. pii: ji2100792. [Epub ahead of print]
      Systemic lupus erythematosus is a complex autoimmune disease with significant morbidity that demands further examination of tolerance-inducing treatments. Short-term treatment of lupus-prone NZB/WF1 mice with combination CTLA4Ig and anti-CD40 ligand, but not single treatment alone, suppresses disease for >6 mo via modulation of B and T cell function while maintaining immune responses to exogenous Ags. Three months after a 2-wk course of combination costimulatory blockade, we found a modest decrease in the number of activated T and B cells in both combination and single-treatment cohorts compared with untreated controls. However, only combination treatment mice showed a 50% decrease in spare respiratory capacity of splenic B and T cells. RNA sequencing and gene set enrichment analysis of germinal center (GC) B cells confirmed a reduction in the oxidative phosphorylation signature in the combination treatment cohort. This cohort also manifested increased expression of BCR-associated signaling molecules and increased phosphorylation of PLCγ in GC B cells after stimulation with anti-IgG and anti-CD40. GC B cells from combination treatment mice also displayed a signature involving remodeling of GPI-linked surface proteins. Accordingly, we found a decrease in cell surface expression of the inhibitory molecule CD24 on class-switched memory B cells from aged NZB/W mice that corrected in the combination treatment cohort. Because both a profound decrease in BCR signaling and remodeled immune cell metabolism enhance loss of tolerance in lupus-prone mice, our findings help to explain the restoration of tolerance observed after short-term combination costimulatory blockade.
  19. PLoS One. 2023 ;18(1): e0280592
      The large-scale dissemination of coronavirus disease-2019 (COVID-19) and its serious complications have pledged the scientific research communities to uncover the pathogenesis mechanisms of its etiologic agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Methods of unveiling such mechanisms are rooted in understanding the viral agent's interactions with the immune system, including its ability to activate macrophages, due to their suggested role in prolonged inflammatory phases and adverse immune responses. The objective of this study is to test the effect of SARS-CoV-2-free proteins on the metabolic and immune responses of macrophages. We hypothesized that SARS-CoV-2 proteins shed during the infection cycle may dynamically induce metabolic and immunologic alterations with an inflammatory impact on the infected host cells. It is imperative to delineate such alterations in the context of macrophages to gain insight into the pathogenesis of these highly infectious viruses and their associated complications and thus, expedite the vaccine and drug therapy advent in combat of viral infections. Human monocyte-derived macrophages were treated with SARS-CoV-2-free proteins at different concentrations. The phenotypic and metabolic alterations in macrophages were investigated and the subsequent metabolic pathways were analyzed. The obtained results indicated that SARS-CoV-2-free proteins induced concentration-dependent alterations in the metabolic and phenotypic profiles of macrophages. Several metabolic pathways were enriched following treatment, including vitamin K, propanoate, and the Warburg effect. These results indicate significant adverse effects driven by residual viral proteins that may hence be considered determinants of viral pathogenesis. These findings provide important insight as to the impact of SARS-CoV-2-free residual proteins on the host cells and suggest a potential new method of management during the infection and prior to vaccination.
  20. Diabetes. 2023 Jan 19. pii: db220054. [Epub ahead of print]
      Innate immune cells infiltrate growing adipose and propagate inflammatory clues to metabolically distant tissues, thereby promoting glucose intolerance and insulin resistance. Cytokines of the IL-6 family and gp130 ligands are among such signals. The role played by Oncostatin M (OSM) in the metabolic consequences of overfeeding is debated at least in part because prior studies did not distinguish OSM sources and dynamics. Here, we explored the role of OSM in metabolic responses and used bone marrow transplantation to test the hypothesis that hematopoietic cells are major contributors to the metabolic effects of OSM. We show that OSM is required to adapt during the development of obesity as OSM concentrations are dynamically modulated during high-fat diet (HFD) and Osm-/- mice displayed early-onset glucose intolerance, impaired muscle glucose uptake, worsened liver inflammation and damage. We found that OSM is mostly produced by blood cells, and that deletion of OSM in hematopoietic cells phenocopied glucose intolerance of whole-body Osm-/- mice on HFD, and recapitulated liver damage with increased aminotransferase levels. We thus uncover that modulation of OSM is involved in the metabolic response to overfeeding and that hematopoietic cell-derived OSM can regulate metabolism, likely via multiple effects in different tissues.
  21. Cell Metab. 2023 Jan 06. pii: S1550-4131(22)00550-2. [Epub ahead of print]
      Although recent studies have highlighted the impact of gut microbes on the progression of obesity and its comorbidities, it is not fully understood how these microbes promote these disorders, especially in terms of the role of microbial metabolites. Here, we report that Fusimonas intestini, a commensal species of the family Lachnospiraceae, is highly colonized in both humans and mice with obesity and hyperglycemia, produces long-chain fatty acids such as elaidate, and consequently facilitates diet-induced obesity. High fat intake altered the expression of microbial genes involved in lipid production, such as the fatty acid metabolism regulator fadR. Monocolonization with a FadR-overexpressing Escherichia coli exacerbated the metabolic phenotypes, suggesting that the change in bacterial lipid metabolism is causally involved in disease progression. Mechanistically, the microbe-derived fatty acids impaired intestinal epithelial integrity to promote metabolic endotoxemia. Our study thus provides a mechanistic linkage between gut commensals and obesity through the overproduction of microbe-derived lipids.
    Keywords:  Lachnospiraceae; gut microbiome; metabolic endotoxemia; microbial metabolite; obesity; tight junction; trans-fatty acid
  22. Biomedicines. 2023 Jan 04. pii: 126. [Epub ahead of print]11(1):
      Inflammation is associated with changes in plasma lipids, lipoproteins, and cholesterol efflux capacity (CEC). It is unknown if the changes in lipids and lipoproteins during inflammation are related to changes in cholesterol absorption, synthesis, and bile acid synthesis. We, therefore, examined the effects of acute lipopolysaccharide (LPS)-induced transient systemic inflammation on lipids, lipoproteins, CEC, and markers of cholesterol metabolism. We also evaluated whether markers for cholesterol metabolism at baseline predict the intensity of the inflammatory response. Eight healthy young subjects received LPS infusion, and blood was sampled for the following 24 h. In addition to lipids, lipoproteins, and CEC, we also measured markers for cholesterol absorption and synthesis, bile acid synthesis, and inflammation. Compared with baseline, plasma total cholesterol, low-density lipoprotein cholesterol, and CEC decreased, while triglycerides increased in the 24 h following LPS infusion. TC-standardized levels of cholesterol synthesis markers (lathosterol, lanosterol, and desmosterol) and a bile acid synthesis marker (7α-OH-cholesterol) also decreased, with no changes in cholesterol absorption markers (campesterol, sitosterol, and cholestanol). Baseline TC-standardized levels of desmosterol and 7α-OH-cholesterol were positively correlated with concentrations of various inflammatory markers. Changes in TC-standardized desmosterol and 7α-OH-cholesterol were negatively correlated with concentrations of inflammatory markers. LPS infusion reduced endogenous cholesterol synthesis and bile acid synthesis in healthy young men.
    Keywords:  LPS-induced inflammation; bile acid synthesis; cholesterol absorption; cholesterol synthesis; non-cholesterol sterols
  23. Cell Death Discov. 2023 Jan 18. 9(1): 10
      Histone deacetylase enzymes (HDACs) regulate protein acetylation. HDAC1 is known to enhance ischemia/reperfusion (I/R) injury, but its underlying mechanism(s) of action have not been defined. Here, in vivo mouse models of myocardial I/R were used to investigate the role of HDAC1 during I/R myocardial injury. We show that HDAC1 enhances the inflammatory responses of I/R mice. Using a constructed macrophage H/R (hypoxia/ regeneration) injury model (Raw264.7 cells), we identified Nur77 as a HDAC1 target in macrophages. Nur77 deficient macrophages failed to downregulate IDH1 (isocitrate dehydrogenase 1) and accumulated succinic acid and other tricarboxylic acid (TCA) cycle-derived metabolites in a glutamine-independent manner. These data show that the inhibition of HDAC1 ameliorates H/R-inflammation in macrophages through the regulation of Nur77 and the TCA cycle.
  24. Fish Shellfish Immunol. 2023 Jan 13. pii: S1050-4648(23)00031-1. [Epub ahead of print]133 108545
      IL-22 has been characterized as a critical cytokine in maintaining barrier integrity and host immunity. So far, it has been known that IL-22 is mainly produced by lymphoid lineage cells. In the present study, we have thoroughly investigated butyrate-induced production and function of IL-22 in fish macrophages. Our results demonstrated that short-chain fatty acids (SCFAs), major microbiota-derived metabolites, promoted the expression of IL-22 in head kidney macrophages (HKMs) of turbot (Scophthalmus maximus L.). Interestingly, butyrate-mediated intracellular bacterial killing in HKMs diminished when IL-22 expression was interfered. Furthermore, the turbot fed the diet containing sodium butyrate (NaB) exhibited significantly lower mortality after bacterial infection, compared to the fish fed a basal diet. At the meantime, a higher level of IL-22 expression and bactericidal activity was detected in HKMs from the turbot fed NaB-supplemented diet. In addition, NaB treatment promoted the expression of antimicrobial peptides (AMPs) β-defensins in zebrafish (Danio rerio). However, butyrate-induced expression of AMPs was reduced in IL-22 mutant zebrafish compared to wild-type (WT) fish. Meanwhile, NaB treatment was incapable to protect IL-22 mutant fish from bacterial infection as it did in WT zebrafish. Importantly, our results demonstrated that IL-22 expression was remarkably suppressed in macrophage-depleted zebrafish, indicating that macrophage might be a cell source of IL-22 production in vivo. In conclusion, all these findings collectively revealed that SCFAs regulated the production and function of IL-22 in fish macrophages, which facilitated host resistance to bacterial invasion.
    Keywords:  Antimicrobial peptides; IL-22; Infection; Macrophage; Short-chain fatty acids (SCFAs)
  25. Biomolecules. 2022 Dec 27. pii: 46. [Epub ahead of print]13(1):
      OBJECTIVES: Prior studies have characterized protein and metabolite changes associated with SARS-CoV-2 infection; we hypothesized that these biomarkers may be part of heritable metabolic pathways in erythrocytes.METHODS: Using a twin study of erythrocyte protein and metabolite levels, we describe the heritability of, and correlations among, previously identified biomarkers that correlate with COVID-19 severity. We used gene ontology and pathway enrichment analysis tools to identify pathways and biological processes enriched among these biomarkers.
    RESULTS: Many COVID-19 biomarkers are highly heritable in erythrocytes. Among heritable metabolites downregulated in COVID-19, metabolites involved in amino acid metabolism and biosynthesis are enriched. Specific amino acid metabolism pathways (valine, leucine, and isoleucine biosynthesis; glycine, serine, and threonine metabolism; and arginine biosynthesis) are heritable in erythrocytes.
    CONCLUSIONS: Metabolic pathways downregulated in COVID-19, particularly amino acid biosynthesis and metabolism pathways, are heritable in erythrocytes. This finding suggests that a component of the variation in COVID-19 severity may be the result of phenotypic variation in heritable metabolic pathways; future studies will be necessary to determine whether individual variation in amino acid metabolism pathways correlates with heritable outcomes of COVID-19.
    Keywords:  COVID-19; SARS-CoV-2; biomarkers; erythrocytes; metabolomics; proteomics
  26. J Clin Invest. 2023 Jan 17. pii: e164577. [Epub ahead of print]133(2):
      Tryptophan (Trp) metabolism plays a central role in sleep, mood, and immune system regulation. The kynurenine pathway (KP), which is regulated by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO), which catalyze the conversion of Trp to kynurenine (Kyn), facilitates immune regulation and influences neurocognition. Notably, Kyn metabolites bind the N-methyl-d-aspartate receptor (NMDAR), essential for memory encoding, and in turn, cognition. Aberrant NMDAR activity through agonist binding influences excitability and cell death. In this issue of the JCI, Watne and authors demonstrate that KP pathway end products were elevated in the serum and the cerebrospinal fluid (CSF) of subjects with delirium. This observation provides insight regarding the basis of a variety of commonly observed clinical conditions including sundowning, abnormal sleep-wake cycles in hospitalized patients, neurodegenerative cognitive impairment, radiation-induced cognitive impairment, neurocognitive symptomatology related to COVID-19, and clinical outcomes observed in patients with CNS tumors, such as gliomas.
  27. Acta Biochim Biophys Sin (Shanghai). 2023 Jan 03.
      <p indent="0mm">The most common cause of death worldwide is atherosclerosis and related cardiovascular disorders. Macrophages are important players in the pathogenesis of atherosclerosis and perform critical functions in iron homeostasis due to recycling iron by phagocytosis of senescent red blood cells and regulating iron availability in the tissue microenvironment. With the growth of research on the "iron hypothesis" of atherosclerosis, macrophage iron has gradually become a hotspot in the refined iron hypothesis. Macrophages with the M1, M2, M(Hb), Mox, and other phenotypes have been defined with different iron-handling capabilities related to the immune function and immunometabolism of macrophages, which influence the progression of atherosclerosis. In this review, we focus on macrophage iron and its effects on the development of atherosclerosis. We also cover the contradictory discoveries and propose a possible explanation. Finally, pharmaceutical modulation of macrophage iron is discussed as a promising target for atherosclerosis therapy.</p>.
    Keywords:  atherosclerosis; iron; macrophage
  28. Elife. 2023 Jan 16. pii: e81320. [Epub ahead of print]12
      Maternal pre-pregnancy (pregravid) obesity is associated with adverse outcomes for both mother and offspring. Amongst the complications for the offspring is increased susceptibility and severity of neonatal infections necessitating admission to the intensive care unit, notably bacterial sepsis and enterocolitis. Previous studies have reported aberrant responses to LPS and polyclonal stimulation by umbilical cord blood monocytes that were mediated by alterations in the epigenome. In this study, we show that pregravid obesity dysregulates umbilical cord blood monocyte responses to bacterial and viral pathogens. Specifically, interferon-stimulated gene expression and inflammatory responses to respiratory syncytial virus (RSV) and E. coli respectively were significantly dampened. Although upstream signaling events were comparable, translocation of the key transcription factor NF-kB and chromatin accessibility at pro-inflammatory gene promoters following TLR stimulation was significantly attenuated. Using a rhesus macaque model of western style diet-induced obesity, we further demonstrate that this defect is detected in fetal peripheral monocytes and tissue-resident macrophages during gestation. Collectively, these data indicate that maternal obesity alters metabolic, signaling, and epigenetic profiles of fetal monocytes leading to a state of immune paralysis during late gestation and at birth.
    Keywords:  chromosomes; gene expression; human; immunology; inflammation; rhesus macaque
  29. Immunometabolism (Cobham). 2023 Jan;5(1): e0016
      Active episodes of inflammatory bowel disease (IBD), which include ulcerative colitis and Crohn's disease, coincide with profound shifts in the composition of the microbiota and host metabolic energy demand. Intestinal epithelial cells (IEC) that line the small intestine and colon serve as an initial point for contact for the microbiota and play a central role in innate immunity. In the 1980s, Roediger et al proposed the hypothesis that IBD represented a disease of diminished mucosal nutrition and energy deficiency ("starved gut") that strongly coincided with the degree of inflammation. These studies informed the scientific community about the important contribution of microbial-derived metabolites, particularly short-chain fatty acids (SCFA) such as butyrate, to overall energy homeostasis. Decades later, it is appreciated that disease-associated shifts in the microbiota, termed dysbiosis, places inordinate demands on energy acquisition within the mucosa, particularly during active inflammation. Here, we review the topic of tissue energetics in mucosal health and disease from the original perspective of that proposed by the starved gut hypothesis.
    Keywords:  butyrate; creatine; epithelium; inflammation; innate immunity colitis; metabolism; microbiota