bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒11‒06
twenty-one papers selected by
Dylan Ryan
University of Cambridge

  1. Nat Commun. 2022 Nov 04. 13(1): 6562
      Itaconate is a newly discovered endogenous metabolite promoting an anti-inflammatory program during innate immune response, but the precise mechanisms underlying its effect remains poorly understood owing primarily to the limitations of available itaconate-monitoring techniques. Here, we develop and validate a genetically encoded fluorescent itaconate biosensor, BioITA, for directly monitoring itaconate dynamics in subcellular compartments of living macrophages. Utilizing BioITA, we monitor the itaconate dynamics in response to lipopolysaccharide (LPS) stimulation in the context of modulating itaconate transportation and metabolism. Moreover, we show that STING activation induces itaconate production, and injection of AAVs expressing cytosolic BioITA into mice allows directly reporting elevation of itaconate level in activated macrophages derived from LPS-injected mice. Thus, BioITA enables subcellular resolution imaging of itaconate in living macrophages.
  2. Nat Metab. 2022 Nov 03.
      Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.
  3. Nat Commun. 2022 Oct 29. 13(1): 6455
      The AKT signaling pathway plays critical roles in the resolution of inflammation. However, the underlying mechanisms of anti-inflammatory regulation and signal coordination remain unclear. Here, we report that anti-inflammatory AKT signaling is coordinated by glutamyl-prolyl-tRNA synthetase 1 (EPRS1). Upon inflammatory activation, AKT specifically phosphorylates Ser999 of EPRS1 in the cytoplasmic multi-tRNA synthetase complex, inducing release of EPRS1. EPRS1 compartmentalizes AKT to early endosomes via selective binding to the endosomal membrane lipid phosphatidylinositol 3-phosphate and assembles an AKT signaling complex specific for anti-inflammatory activity. These events promote AKT activation-mediated GSK3β phosphorylation, which increase anti-inflammatory cytokine production. EPRS1-deficient macrophages do not assemble the early endosomal complex and consequently exacerbate inflammation, decreasing the survival of EPRS1-deficient mice undergoing septic shock and ulcerative colitis. Collectively, our findings show that the housekeeping protein EPRS1 acts as a mediator of inflammatory homeostasis by coordinating compartment-specific AKT signaling.
  4. Front Immunol. 2022 ;13 1019365
      The inflammasome has been linked to diverse inflammatory and metabolic diseases, and tight control of inflammasome activation is necessary to avoid excessive inflammation. Kynurenic acid (KA) is a tryptophan metabolite in the kynurenine pathway. However, the roles and mechanisms of the regulation of inflammasome activation by KA have not yet been fully elucidated. Here, we found that KA suppressed caspase-1 activation and IL-1β production in macrophages by specifically inhibiting canonical and noncanonical activation of the NLRP3 inflammasome. Mechanistically, KA reduced calcium mobilization through G-protein receptor 35 (GPR35), resulting in reduced mitochondrial damage and decreased mtROS production, thus blocking NLRP3 inflammasome assembly and activation. Importantly, KA prevented lipopolysaccharide-induced systemic inflammation, monosodium urate-induced peritoneal inflammation, and high-fat diet-induced metabolic disorder. Thus, KA ameliorated inflammation and metabolic disorders by blocking calcium mobilization-mediated NLRP3 inflammasome activation via GPR35. Our data reveal a novel mechanism for KA in the modulation of inflammasome activation and suggest that GPR35 might be a promising target for improving NLRP3 inflammasome-associated diseases by regulating calcium mobilization.
    Keywords:  GPR35; NLRP3 inflammasome; kynurenic acid; metabolic disorder; systemic inflammation
  5. Virology. 2022 Oct 27. pii: S0042-6822(22)00183-0. [Epub ahead of print]577 84-90
      Itaconate, a metabolite of the tricarboxylic acid (TCA) cycle produced by immunoresponsive gene 1 (IRG1) via catalyzation of cis-aconitate, plays important roles in metabolism and immunity. Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has devastated the swine industry worldwide for over 30 years. Here, we found that 4-octyl itaconate (4-OI), a cell-permeable itaconate derivative, dose-dependently inhibited PRRSV proliferation by interfering with viral attachment, replication, and release. Furthermore, 4-OI suppressed the PRRSV-induced inflammatory response by enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Interestingly, PRRSV infection caused a reduction in itaconate abundance and simultaneously led to an accumulation of cis-aconitate, the upstream metabolite of itaconate, and both of these effects were accomplished by downregulating IRG1 expression. Taken together, these results demonstrate that 4-OI not only inhibits PRRSV replication but also suppresses PRRSV-induced inflammatory responses, indicating that 4-OI is a promising drug candidate for combating PRRSV.
    Keywords:  4-octyl itaconate (4-OI); Immunoresponsive gene 1 (IRG1); Itaconate; Nuclear factor-erythroid 2-related factor 2 (Nrf2); Porcine reproductive and respiratory syndrome virus (PRRSV)
  6. Front Immunol. 2022 ;13 966158
      Macrophages are prominent immune cells in the tumor microenvironment that can be educated into pro-tumoral phenotype by tumor cells to favor tumor growth and metastasis. The mechanisms that mediate a mutualistic relationship between tumor cells and macrophages remain poorly characterized. Here, we have shown in vitro that different human and murine cancer cell lines release branched-chain α-ketoacids (BCKAs) into the extracellular milieu, which influence macrophage polarization in an monocarboxylate transporter 1 (MCT1)-dependent manner. We found that α-ketoisocaproate (KIC) and α-keto-β-methylvalerate (KMV) induced a pro-tumoral macrophage state, whereas α-ketoisovalerate (KIV) exerted a pro-inflammatory effect on macrophages. This process was further investigated by a combined metabolomics/proteomics platform. Uptake of KMV and KIC fueled macrophage tricarboxylic acid (TCA) cycle intermediates and increased polyamine metabolism. Proteomic and pathway analyses revealed that the three BCKAs, especially KMV, exhibited divergent effects on the inflammatory signal pathways, phagocytosis, apoptosis and redox balance. These findings uncover cancer-derived BCKAs as novel determinants for macrophage polarization with potential to be selectively exploited for optimizing antitumor immune responses.
    Keywords:  BCKAs Fc-gamma receptor (FCgR)-mediated phagocytosis; apoptosis; macrophage polarization; panomics; tumor necrosis factor alpha (TNFα)-nuclear factor kappa B (NFκB) -mediated inflammatory pathway; tumor-associated macrophages
  7. Front Immunol. 2022 ;13 1012442
      Inflammation plays an important role in the occurrence and development of neuropathic pain. Immune-responsive gene 1 (IRG1) decarboxylates cis-aconitate to produce itaconate in the mitochondria. Itaconate serves as an immunomodulator of macrophages and represses inflammation in infectious diseases. Recently, a study showed that an itaconate derivative inhibits neuroinflammation and reduces chronic pain in mice. However, the function and molecular mechanisms of endogenous itaconate in neuropathic pain have not been fullyelucidated. In this study, the content of itaconate in the ipsilateral spinal cord after nerve-injured mice was detected with mass spectrometry. The Irg1-/- mouse was constructed to determine the role of endogenous itaconate in the chronic constriction nerve injury (CCI) model. The analgesic effect of exogenous itaconate was assessed with intraperitoneal and intrathecal administration in both male and female CCI mice. The spinal application of 4-OI also reduced the evoked responses of wide dynamic range neurons in CCI mice. The potential analgesic mechanism of itaconate was explored through molecular biology experiments and verified in Interleukin (IL)-10-/- mice. We found the levels of itaconate and IRG1 in the spinal cord significantly increased after CCI. Irg1 deficiency aggravated the mechanical and heat hypersensitivity, while the exogenous administration of the itaconate derivative 4-OI alleviated the neuropathic pain in male and female CCI mice. Mechanistically, the treatment of 4-OI increased the level of IL-10 and activates STAT3/β-endorphin pathway in the spinal cord, and the analgesia effect of itaconate was impaired in IL-10-/- mice. Finally, we showed that the upregulation of IL-10 induced by 4-OI was mainly from spinal neurons through Nrf2 pathway. This study demonstrated the analgesic effect of endogenous and exogenous itaconate in the neuropathic pain model, suggesting that the spinal IL-10/STAT3/β-endorphin pathway might mediate the analgesia effect of itaconate.
    Keywords:  IRG1; interleukin-10; itaconate; neuropathic pain; tricarboxylic acid cycle
  8. Immunol Med. 2022 Nov 03. 1-10
      T helper 17 (Th17) cells are IL-17-producing CD4 T cells that play a crucial role in autoimmune diseases. IL-17 is a key cytokine for host protection against mucosal and skin infection but is also one of the major pathogenic cytokines. IL-1 and IL-23 are requisite for stimulating pathogenic Th17 cell differentiation and proliferation. Therapeutics targeting the IL-17/IL-23 pathway are widely used clinically for the treatment of autoimmune diseases. Besides IL-17, pathogenic Th17 cells produce granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, interferon γ, IL-21 and IL-22. However, Th17-targeted therapy has not yet been established. T cell metabolism orchestrates T cell survival, cell differentiation, epigenetic change and function and each T cell subset favors a particular metabolic pathway. Recent studies have provided novel insights into the role of T cell metabolism in the pathogenesis of autoimmune diseases. The current review focuses on the role of Th17 cell metabolism in autoimmune diseases, particularly glycolysis, amino acid metabolism, lipid metabolism, as well as the regulators of these processes, including mTORC1. Therapeutics targeting T cell metabolism in autoimmune diseases could serve as a possible treatment option for patients who are refractory to or unresponsive to conventional therapy.
    Keywords:  Cellular metabolism; IL-17; Th17; glutaminolysis; glycolysis
  9. Front Microbiol. 2022 ;13 975436
      T cells orchestrate adaptive and innate immune responses against pathogens and transformed cells. However, T cells are also the main adaptive effector cells that mediate allergic and autoimmune reactions. Within the last few years, it has become abundantly clear that activation, differentiation, effector function, and environmental adaptation of T cells is closely linked to their energy metabolism. Beyond the provision of energy equivalents, metabolic pathways in T cells generate building blocks required for clonal expansion. Furthermore, metabolic intermediates directly serve as a source for epigenetic gene regulation by histone and DNA modification mechanisms. To date, several antibiotics were demonstrated to modulate the metabolism of T cells especially by altering mitochondrial function. Here, we set out to systematically review current evidence about how beta-lactam antibiotics, macrolides, fluoroquinolones, tetracyclines, oxazolidinones, nitroimidazoles, and amphenicols alter the metabolism and effector functions of CD4+ T helper cell populations and CD8+ T cells in vitro and in vivo. Based on this evidence, we have developed an overview on how the use of these antibiotics may be beneficial or detrimental in T cell-mediated physiological and pathogenic immune responses, such as allergic and autoimmune diseases, by altering the metabolism of different T cell populations.
    Keywords:  T cells; antibiotics; bacteria; host-pathogen; metabolism; mitochondria
  10. Reprod Med Biol. 2022 Jan-Dec;21(1):21(1): e12488
      Background: Endometriosis is an estrogen-dependent disease and causes pelvic pain and infertility. The limits of current pharmacotherapy in women who desire to become pregnant prompt the development of various targeted molecules for more effective treatment. A review article focused on the unique aspect of cellular metabolic reprogramming of endometriotic cells has been reported. The cellular metabolic pathways are reprogrammed to adapt to a variety of environmental stresses (e.g., nutrient starvation or glucose deprivation, hypoxic stress, excessive reactive oxygen species generation, and other environmental factors). This review aims to summarize macrophage polarization and metabolic reprogramming in endometriosis.Methods: A literature search was performed between January 2000 and March 2022 in the PubMed and Google Scholar databases using a combination of specific terms.
    Results: Macrophage cellular metabolism has a marked influence on its phenotype and function. Preclinical studies showed that metabolic conversion toward glycolysis or oxidative phosphorylation drives macrophage polarization to M1 or M2 phenotype, respectively. Such cellular metabolic rewiring can offer new therapeutic opportunities.
    Conclusion: A better understanding of metabolic reprogramming biology in endometriosis-associated macrophages is essential in considering novel therapeutic approach for endometriosis. However, there are currently no detailed studies on therapeutic strategies targeting the cellular metabolic properties of endometriosis-associated macrophages.
    Keywords:  endometriosis; macrophages; metabolic reprogramming; phenotype
  11. Cancer Discov. 2022 Nov 04. OF1
      Spermidine enhances T-cell mitochondrial metabolism and the antitumor response to anti-PD-L1.
  12. Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00460-0. [Epub ahead of print]34(11): 1613-1615
      Diverse ion channels have dysregulated functional expression in the tumor microenvironment (TME). In this issue of Cell Metabolism, Chen et al. reveal that high intratumoral K+ ions restrict the plasticity of tumor-associated macrophages (TAMs). Inhibition of the Kir2.1 potassium channel induced metabolic reprogramming and repolarization of pro-tumor M2-TAMs to tumoricidal M1-like states.
  13. Front Immunol. 2022 ;13 932055
      Recent findings about the new roles of lactate have changed our understanding of this end product of glycolysis or fermentation that was once considered only a waste product. It is now well accepted that lactate acts as a signaling molecule and fuel source for cancer cells in a glucose-restricted environment. Moreover, lactate and lactate dehydrogenase are markers of poor prognosis of many cancers and regulate many functions of immune cells. The presence of lactate in the tumor microenvironment (TME) leads to polarization of the immunosuppressive phenotypes of dendritic cells and impairs the cytotoxic abilities of T cells and NK cells, and as such lactate is a major obstacle to immune-cell effector functions and the efficacy of cell-based immunotherapies. Emerging evidence suggests that lactate in the TME might be a novel therapeutic target to enhance the immunotherapeutic potential of cell-based therapies. This review describes our current understanding of the role of lactate in tumor biology, including its detrimental effects on cell-based immunotherapy in cancer. We also highlight how the role of lactate in the TME must be considered when producing cell therapies designed for adoptive transfer and describe how targeted modulation of lactate in the TME might boost immune-cell functions and positively impact cellular immunotherapy, with a focus on NK cell.
    Keywords:  NK cell; T cell; cytotoxicity; immunometabolism; immunosuppression,; immunotherapy; lactate
  14. Immunol Rev. 2022 Nov 03.
      Neutrophils are a critical element of host defense and are rapidly recruited to inflammatory sites. Such sites are frequently limited in oxygen and/or nutrient availability, presenting a metabolic challenge for infiltrating cells. Long believed to be uniquely dependent on glycolysis, it is now clear that neutrophils possess far greater metabolic plasticity than previously thought, with the capacity to generate energy stores and utilize extracellular proteins to fuel central carbon metabolism and biosynthetic activity. Out-with cellular energetics, metabolic programs have also been implicated in the production of neutrophils and their progenitors in the bone marrow compartment, activation of neutrophil antimicrobial responses, inflammatory and cell survival signaling cascades, and training of the innate immune response. Thus, understanding the mechanisms by which metabolic processes sustain changes in neutrophil effector functions and how these are subverted in disease states provides exciting new avenues for the treatment of dysfunctional neutrophilic inflammation which are lacking in clinical practice to date.
    Keywords:  immunometabolism; inflammation; neutrophil; trained immunity
  15. Front Immunol. 2022 ;13 990794
      The immune system protects from infections and cancer through complex cellular networks. For this purpose, immune cells require well-developed mechanisms of energy generation. However, the immune system itself can also cause diseases when defective regulation results in the emergence of autoreactive lymphocytes. Recent studies provide insights into how differential patterns of immune cell responses are associated with selective metabolic pathways. This review will examine the changing metabolic requirements of Th17 cells and of B cells at different stages of their development and activation. Both cells provide protection but can also mediate diseases through the production of autoantibodies and the production of proinflammatory mediators. In health, B cells produce antibodies and cytokines and present antigens to T cells to mount specific immunity. Th17 cells, on the other hand, provide protection against extra cellular pathogens at mucosal surfaces but can also drive chronic inflammation. The latter cells can also promote the differentiation of B cells to plasma cells to produce more autoantibodies. Metabolism-regulated checkpoints at different stages of their development ensure the that self-reactive B cells clones and needless production of interleukin (IL-)17 are limited. The metabolic regulation of the two cell types has some similarities, e.g. the utility of hypoxia induced factor (HIF)1α during low oxygen tension, to prevent autoimmunity and regulate inflammation. There are also clear differences, as Th17 cells only are vulnerable to the lack of certain amino acids. B cells, unlike Th17 cells, are also dependent of mechanistic target of rapamycin 2 (mTORC2) to function. Significant knowledge has recently been gained, particularly on Th17 cells, on how metabolism regulates these cells through influencing their epigenome. Metabolic dysregulation of Th17 cells and B cells can lead to chronic inflammation. Disease associated alterations in the genome can, in addition, cause dysregulation to metabolism and, thereby, result in epigenetic alterations in these cells. Recent studies highlight how pathology can result from the cooperation between the two cell types but only few have so far addressed the key metabolic alterations in such settings. Knowledge of the impact of metabolic dysfunction on chronic inflammation and pathology can reveal novel therapeutic targets to treat such diseases.
    Keywords:  B cells; OXPHOS; Th17 cells; autoimmunity; epigenetics; mTORC; metabolism
  16. J Immunol. 2022 Nov 04. pii: ji2100669. [Epub ahead of print]
      The mechanistic target of rapamycin is an essential regulator of T cell metabolism and differentiation. In this study, we demonstrate that serum- and glucocorticoid-regulated kinase 1 (SGK1), a downstream node of mechanistic target of rapamycin complex 2 signaling, represses memory CD8+ T cell differentiation. During acute infections, murine SGK1-deficient CD8+ T cells adopt an early memory precursor phenotype leading to more long-lived memory T cells. Thus, SGK1-deficient CD8+ T cells demonstrate an enhanced recall capacity in response to reinfection and can readily reject tumors. Mechanistically, activation of SGK1-deficient CD8+ T cells results in decreased Foxo1 phosphorylation and increased nuclear translocation of Foxo1 to promote early memory development. Overall, SGK1 might prove to be a powerful target for enhancing the efficacy of vaccines and tumor immunotherapy.
  17. Kidney Int. 2022 Nov 01. pii: S0085-2538(22)00913-9. [Epub ahead of print]
      Current treatment strategies for autoimmune diseases may not sufficiently control aberrant metabolism in B-cells. To address this concern, we investigated a biguanide derivative, IM156, as a potential regulator for B-cell metabolism in vitro and in vivo on overactive B-cells stimulated by the pro-inflammatory receptor TLR-9 agonist CpG oligodeoxynucleotide, a mimic of viral/bacterial DNA. Using RNA sequencing, we analyzed the B-cell transcriptome expression, identifying the major molecular pathways affected by IM156 in vivo. We also evaluated the anti-inflammatory effects of IM156 in lupus-prone NZB/W F1 mice. CD19+B-cells exhibited higher mitochondrial mass and mitochondrial membrane potential compared to T-cells and were more susceptible to IM156-mediated oxidative phosphorylation inhibition. In vivo, IM156 inhibited mitochondrial oxidative phosphorylation, cell cycle progression, plasmablast differentiation, and activation marker levels in CpG oligodeoxynucleotide-stimulated mouse spleen B-cells. Interestingly, IM156 treatment significantly increased overall survival, reduced glomerulonephritis and inhibited B-cell activation in the NZB/W F1 mice. Thus, our data indicated that IM156 suppressed the mitochondrial membrane potentials of activated B-cells in mice, contributing to the mitigation of lupus activity. Hence, IM156 may represent a therapeutic alternative for autoimmune disease mediated by B-cell hyperactivity.
    Keywords:  B-cell metabolism; IM156; autoimmune diseases; systemic lupus erythematosus
  18. Trends Immunol. 2022 Oct 29. pii: S1471-4906(22)00213-7. [Epub ahead of print]
      Lactic acid production has been regarded as a mechanism by which malignant cells escape immunosurveillance. Recent technological advances in mass spectrometry and the use of cell culture media with a physiological nutrient composition have shed new light on the role of lactic acid and its conjugate lactate in the tumor microenvironment. Here, we review novel work identifying lactate as a physiological carbon source for mammalian tumors and immune cells. We highlight evidence that its use as a substrate is distinct from the immunosuppressive acidification of the extracellular milieu by lactic acid protons. Together, data suggest that neutralizing the effects of intratumoral acidity while maintaining physiological lactate metabolism in cytotoxic CD8+ T cells should be pursued to boost anti-tumor immunity.
  19. PLoS One. 2022 ;17(11): e0277251
      GPR40, a G protein-coupled receptor for free fatty acids (FFAs), is considered as a therapeutic target for type 2 diabetes mellitus (T2DM) since GPR40 activation in pancreatic beta cells enhances glucose-stimulated insulin secretion. Nonalcoholic fatty liver disease (NAFLD) is a common complication of T2DM or metabolic syndrome (MetS). However, the role of GPR40 in NAFLD associated with T2DM or MetS has not been well established. Given that it is known that cholesterol and FFAs are critically involved in the pathogenesis of nonalcoholic steatohepatitis (NASH) and LDL receptor (LDLR)-deficient mice are a good animal model for human hyperlipidemia including high cholesterol and FFAs, we generated GPR40 and LDLR double knockout (KO) mice in this study to determine the effect of GPR40 KO on hyperlipidemia-promoted NASH. We showed that GPR40 KO increased plasma levels of cholesterol and FFAs in high-fat diet (HFD)-fed LDLR-deficient mice. We also showed that GPR40 KO exacerbated HFD-induced hepatic steatosis, inflammation and fibrosis. Further study demonstrated that GPR40 KO led to upregulation of hepatic CD36 and genes involved in lipogenesis, fatty acid oxidation, fibrosis and inflammation. Finally, our in vitro mechanistic studies showed that while CD36 was involved in upregulation of proinflammatory molecules in macrophages by palmitic acid (PA) and lipopolysaccharide (LPS), GPR40 activation in macrophages exerts anti-inflammatory effects. Taken together, this study demonstrated for the first time that loss of GPR40 in LDLR-deficient mice exacerbated HFD-induced hyperlipidemia, hepatic steatosis, inflammation and fibrosis potentially through a CD36-dependent mechanism, suggesting that GPR40 may play a beneficial role in hyperlipidemia-associated NASH in LDLR-deficient mice.
  20. Front Immunol. 2022 ;13 1013686
      Background: Lactate has long been considered an intermediate by-product of glucose metabolism. However, in recent years, accumulating evidence reveals that lactate has unique biological activities. In previous studies, lactate signaling was shown to inhibit inflammation. Furthermore, in vitro experiments have shown that lactate can promote the transformation of pro-inflammatory macrophages into anti-inflammatory macrophages. However, no in vivo studies have shown whether lactate can alleviate inflammation.Methods: RAW 264.7 macrophages were stimulated by LPS to induce an M1 phenotype, and cultured with low and high concentrations of lactate. The cells were then observed for phenotypic transformations and expression of inflammatory mediators and surface markers. The expression of inflammatory factors was also analyzed in the cell-free supernatant fraction. Further, a mouse model of DSS-induced colitis was established and treated with lactate. Colonic tissue injury was monitored by histopathological examinations.
    Results: The in vitro experiments showed that lactate promoted the transformation of activated macrophages to M2 phenotype and decreased the expression of TLR4-mediated NF-κB signaling proteins and inflammatory factors. In the DSS-induced colitis mouse model, lactate promoted the phenotypic transformation of macrophages in colonic tissue, reduced inflammation and organ damage, inhibited the activation of TLR4/NF-κB signaling pathway, decreased the serum levels of pro-inflammatory factors, increased the expression of anti-inflammatory factors, promoted the repair of the intestinal mucosal barrier and reduced the severity of colitis.
    Conclusions: Lactate inhibits the TLR/NF-κB signaling pathway and the production of pro-inflammatory factors by promoting polarization of macrophages. In addition, lactate promotesthe repair of the intestinal mucosal barrier and protects intestinal tissue in inflammation. Furthermore, lactate is relatively safe. Therefore, lactate is a promising and effective drug for treating inflammation through immunometabolism regulation.
    Keywords:  colitis; inflammation; inflammatory microenvironment; lactic acid; macrophage polarization
  21. Cell Mol Gastroenterol Hepatol. 2022 Oct 31. pii: S2352-345X(22)00214-4. [Epub ahead of print]