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Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity.

ABSTRACT: Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deficiency of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived interleukin-22 (IL-22) production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22+ CCR6+ ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings suggest that Ffar2 regulates colonic ILC3 proliferation and function, and they identify an ILC3-receptor signaling pathway modulating gut homeostasis and pathogen defense.

SUBMITTER: Chun E

PROVIDER: S-EPMC6901086 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Metabolite - sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity

Project description:Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deletion of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived IL-22 production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22+ CCR6+ ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings demonstrate that Ffar2 regulates colonic ILC3 proliferation and function in a cell-intrinsic manner and identifies an ILC3-receptor signaling pathway regulating gut inflammatory tone and pathogen defense.

2019-09-16 | GSE137508 | GEO

The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells.

Project description:Innate lymphoid cells (ILCs) expressing the nuclear receptor ROR?t are essential for gut immunity presumably through production of interleukin-22 (IL-22). The molecular mechanism underlying the development of ROR?t(+) ILCs is poorly understood. Here, we have shown that the aryl hydrocarbon receptor (Ahr) plays an essential role in ROR?t(+) ILC maintenance and function. Expression of Ahr in the hematopoietic compartment was important for accumulation of adult but not fetal intestinal ROR?t(+) ILCs. Without Ahr, ROR?t(+) ILCs had increased apoptosis and less production of IL-22. ROR?t interacted with Ahr and promoted Ahr binding at the Il22 locus. Upon IL-23 stimulation, Ahr-deficient ROR?t(+) ILCs had reduced IL-22 expression, consistent with downregulation of IL-23R in those cells. Ahr-deficient mice succumbed to Citrobacter rodentium infection, whereas ectopic expression of IL-22 protected animals from early mortality. Our data uncover a previously unrecognized physiological role for Ahr in promoting innate gut immunity by regulating ROR?t(+) ILCs.

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Ketogenic diet alleviates colitis by reduction of colonic group 3 innate lymphoid cells through altering gut microbiome.

Project description:Accumulating evidence suggests that ketogenic diets (KDs) mediate the rise of circulating ketone bodies and exert a potential anti-inflammatory effect; however, the consequences of this unique diet on colitis remain unknown. We performed a series of systematic studies using a dextran sulfate sodium (DSS) animal model of inflammatory colitis. Animals were fed with a KD, low-carbohydrate diet (LCD), or normal diet (ND). Germ-free mice were utilized in validation experiments. Colon tissues were analyzed by transcriptome sequencing, RT2 profiler PCR array, histopathology, and immunofluorescence. Serum samples were analyzed by metabolic assay kit. Fecal samples were analyzed by 16S rRNA gene sequencing, liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. We observed that KD alleviated colitis by altering the gut microbiota and metabolites in a manner distinct from LCD. Quantitative diet experiments confirmed the unique impact of KD relative to LCD with a reproducible increase in Akkermansia, whereas the opposite was observed for Escherichia/Shigella. After colitis induction, the KD protected intestinal barrier function, and reduced the production of RORγt+CD3- group 3 innate lymphoid cells (ILC3s) and related inflammatory cytokines (IL-17α, IL-18, IL-22, Ccl4). Finally, fecal microbiota transplantation into germ-free mice revealed that the KD- mediated colitis inhibition and ILC3 regulation were dependent on the modification of gut microbiota. Taken together, our study presents a global view of microbiome-metabolomics changes that occur during KD colitis treatment, and identifies the regulation of gut microbiome and ILC3s as novel targets involving in IBD dietary therapy.

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G9a regulates group 2 innate lymphoid cell development by repressing the group 3 innate lymphoid cell program.

Project description:Innate lymphoid cells (ILCs) are emerging as important regulators of homeostatic and disease-associated immune processes. Despite recent advances in defining the molecular pathways that control development and function of ILCs, the epigenetic mechanisms that regulate ILC biology are unknown. Here, we identify a role for the lysine methyltransferase G9a in regulating ILC2 development and function. Mice with a hematopoietic cell-specific deletion of G9a (Vav.G9a(-/-) mice) have a severe reduction in ILC2s in peripheral sites, associated with impaired development of immature ILC2s in the bone marrow. Accordingly, Vav.G9a(-/-) mice are resistant to the development of allergic lung inflammation. G9a-dependent dimethylation of histone 3 lysine 9 (H3K9me2) is a repressive histone mark that is associated with gene silencing. Genome-wide expression analysis demonstrated that the absence of G9a led to increased expression of ILC3-associated genes in developing ILC2 populations. Further, we found high levels of G9a-dependent H3K9me2 at ILC3-specific genetic loci, demonstrating that G9a-mediated repression of ILC3-associated genes is critical for the optimal development of ILC2s. Together, these results provide the first identification of an epigenetic regulatory mechanism in ILC development and function.

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Group 2 Innate Lymphoid Cells (ILC2): Type 2 Immunity and Helminth Immunity.

Project description:Group 2 innate lymphoid cells (ILC2) have emerged as a major component of type 2 inflammation in mice and humans. ILC2 secrete large amounts of interleukins 5 and 13, which are largely responsible for host protective immunity against helminth parasites because these cytokines induce profound changes in host physiology that include: goblet cell metaplasia, mucus accumulation, smooth muscle hypercontractility, eosinophil and mast cell recruitment, and alternative macrophage activation (M2). This review covers the initial recognition of ILC2 as a distinct cell lineage, the key studies that established their biological importance, particularly in helminth infection, and the new directions that are likely to be the focus of emerging work that further explores this unique cell population in the context of health and disease.

| S-EPMC6539149 | biostudies-literature

CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut.

Project description:Fetal CD4(+) lymphoid tissue inducer (LTi) cells play a critical role in the development of lymphoid tissues. Recent studies identified that LTi cells persist in adults and are related to a heterogeneous population of innate lymphoid cells that have been implicated in inflammatory responses. However, whether LTi cells contribute to protective immunity remains poorly defined. We demonstrate that after infection with Citrobacter rodentium, CD4(+) LTi cells were a dominant source of interleukin-22 (IL-22) early during infection. Infection-induced CD4(+) LTi cell responses were IL-23 dependent, and ablation of IL-23 impaired innate immunity. Further, depletion of CD4(+) LTi cells abrogated infection-induced expression of IL-22 and antimicrobial peptides, resulting in exacerbated host mortality. LTi cells were also found to be essential for host protective immunity in lymphocyte-replete hosts. Collectively these data demonstrate that adult CD4(+) LTi cells are a critical source of IL-22 and identify a previously unrecognized function for CD4(+) LTi cells in promoting innate immunity in the intestine.

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Group 3 innate lymphoid cells mediate early protective immunity against tuberculosis.

Project description:Tuberculosis is the leading cause of death by an infectious disease worldwide1. However, the involvement of innate lymphoid cells (ILCs) in immune responses to infection with Mycobacterium tuberculosis (Mtb) is unknown. Here we show that circulating subsets of ILCs are depleted from the blood of participants with pulmonary tuberculosis and restored upon treatment. Tuberculosis increased accumulation of ILC subsets in the human lung, coinciding with a robust transcriptional response to infection, including a role in orchestrating the recruitment of immune subsets. Using mouse models, we show that group 3 ILCs (ILC3s) accumulated rapidly in Mtb-infected lungs and coincided with the accumulation of alveolar macrophages. Notably, mice that lacked ILC3s exhibited a reduction in the accumulation of early alveolar macrophages and decreased Mtb control. We show that the C-X-C motif chemokine receptor 5 (CXCR5)-C-X-C motif chemokine ligand 13 (CXCL13) axis is involved in Mtb control, as infection upregulates CXCR5 on circulating ILC3s and increases plasma levels of its ligand, CXCL13, in humans. Moreover, interleukin-23-dependent expansion of ILC3s in mice and production of interleukin-17 and interleukin-22 were found to be critical inducers of lung CXCL13, early innate immunity and the formation of protective lymphoid follicles within granulomas. Thus, we demonstrate an early protective role for ILC3s in immunity to Mtb infection.

| S-EPMC6626542 | biostudies-literature

Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation.

Project description:Group 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7?,25-hydroxycholesterol (7?,25-OHC). In mice lacking Gpr183 or 7?,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Gpr183 deficiency in ILC3s caused a defect in CP and ILF formation in the colon, but not in the small intestine. Localized oxysterol production by fibroblastic stromal cells provided an essential signal for colonic lymphoid tissue development, and inflammation-induced increased oxysterol production caused colitis through GPR183-mediated cell recruitment. Our findings show that GPR183 promotes lymphoid organ development and indicate that oxysterol-GPR183-dependent positioning within tissues controls ILC3 activity and intestinal homeostasis.

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Project description:Group 1 Innate Lymphoid Cells (which include Natural Killer cells and ILC1s) aid in gut anti-bacterial defense through the production of IFNγ, which is critical for mobilizing protective responses against enteric pathogens. When intestinal epithelial barrier integrity is compromised, commensal bacteria are likely to translocate from the gut lumen into the lamina propria. Few studies have addressed the mechanisms by which commensal bacteria impact the function of gut Group 1 ILCs, especially ILC1s. Utilizing an in vitro human colonic lamina propria mononuclear cell (LPMC) model, we evaluated Group 1 ILC cytokine and cytolytic protein production in response to a panel of enteric Gram-positive and Gram-negative commensal and pathogenic bacteria. IFNγ-production by NK cells and ILC1s was significantly increased after LPMC exposure to Gram-negative commensal or pathogenic bacteria, but not after exposure to the Gram-positive bacteria commensals tested. Stimulation of IFNγ production from Group 1 ILCs was not through direct recognition of bacteria by NK cells or ILC1s, but rather required accessory cells within the LPMC population. Myeloid dendritic cells generated IL-12p70, IL-18, and IL-1β upon exposure to enteric bacteria and these cytokines contributed to Group 1 ILC production of IFNγ. Furthermore, Gram-negative commensal or pathogenic bacteria induced significant expression of Granzyme B in NK cells and ILC1s. Overall, these data demonstrate that some enteric commensal bacteria indirectly induce inflammatory cytokine production and cytolytic protein expression from human colonic Group 1 ILCs, a process which could contribute to inflammation in the setting of microbial translocation.

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Project description:Group 2 innate lymphoid cells (ILC-2s) regulate immune responses to pathogens and maintain tissue homeostasis in response to cytokines. Positive regulation of ILC-2s through ICOS has been recently elucidated. We demonstrate here that PD-1 is an important negative regulator of KLRG1+ ILC-2 function in both mice and humans. Increase in KLRG1+ ILC-2 cell numbers was attributed to an intrinsic defect in PD-1 signaling, which resulted in enhanced STAT5 activation. During Nippostrongylus brasiliensis infection, a significant expansion of KLRG1+ ILC-2 subsets occurred in Pdcd1-/- mice and, upon adoptive transfer, Pdcd1-/- KLRG1+ ILC-2s significantly reduced worm burden. Furthermore, blocking PD-1 with an antibody increased KLRG1+ ILC-2 cell number and reduced disease burden. Therefore, PD-1 is required for maintaining the number, and hence function, of KLRG1+ ILC-2s.

| S-EPMC5461001 | biostudies-literature

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