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  • Recent studies support the concept that dietary

    2020-10-16

    Recent studies support the concept that dietary metabolites, such as retinoids and AHR ligands, regulate ILC3 function. These metabolites act through intracellular nuclear receptors that function as transcription factors, thereby controlling ILC activity through the stimulation of specific transcriptional programs. We have now shown that endogenous metabolites derived from cholesterol control ILC3 function by binding to a cell-surface receptor (GPR183). Previously, it was found that 7α,27-OHC and 7β,27-OHC can act as endogenous RORγt agonists and thereby regulate Th17 differentiation (Soroosh et al., 2014). More recently, it was reported that CYP51-dependent intermediates in cholesterol biosynthesis are ligands for RORγt (Santori et al., 2015). Chemically distinct cholesterol metabolites can therefore be sensed intracellularly through RORγt (modulating cell differentiation) and extracellularly through GPR183 (controlling ILC3 migration). ILC3s have been implicated in gut inflammation in various mouse models of colitis (Buonocore et al., 2010, Powell et al., 2012, Vonarbourg et al., 2010) as well as in humans with IBD (Geremia et al., 2011). Furthermore, intestinal inflammation is associated with the expansion of lymphoid structures in the gut, and hyperplastic lymphoid Maraviroc have been observed in human IBD (Buettner and Lochner, 2016). We demonstrated that GPR183 promotes lymphoid tissue formation by ILC3s not only during steady state but also during inflammation. Our findings support the notion that GPR183 stimulates pro-inflammatory ILC3 activity in the colon by triggering an inflammatory migratory response that is reminiscent of the postnatal clustering of ILC3s during the formation of CPs and ILFs. Interestingly, a Gpr183 polymorphism has been associated with IBD in humans (Jostins et al., 2012), supporting the idea that GPR183 promotes intestinal inflammation.
    STAR★Methods
    Acknowledgments We thank A. Rongvaux, L. Evangelisti, J. Stein, C. Hughes, and L. Borelli for help with generating Gpr183−/− mice. We also thank L. Zenewicz for providing cDNA and G. Eberl (Pasteur Institute) for providing Rorc(γt) transgenic mice. R.A.F. is an investigator of the Howard Hughes Medical Institute. This work was supported by a Sir Henry Dale Wellcome Trust Fellowship (105644/Z/14/Z) to M.R.H., NIH grant RO1AI113040 to J.P.P., Swiss National Science Foundation grant 159188 to B.L., and a Junior Investigator Research Grant from the Center for Innovative Medicine at the Karolinska Institutet and a grant from the Åke Wiberg Foundation to T.W.
    Introduction The intestinal mucosal barrier surface is constantly exposed to food antigens, beneficial microbes, pathogens, and a multitude of other environmental stimuli (Turner, 2009). Innate lymphoid cells (ILCs) are known to contribute to innate and adaptive immune responses against these stimuli and play a critical role in maintaining barrier function and intestinal homeostasis (Artis and Spits, 2015, Diefenbach et al., 2014, Eberl et al., 2015, Klose and Artis, 2016, Spits et al., 2013, Spits et al., 2016). ILCs are lineage-negative (Lin−), interleukin-7 (IL-7) receptor α-positive (CD127+), CD90+ innate immune cells that are widely distributed throughout the body, particularly enriched at the mucosal barriers (Artis and Spits, 2015, Diefenbach et al., 2014, Eberl et al., 2015, Klose and Artis, 2016). Group 3 ILCs (ILC3s) express the transcription factor RORγt and play pivotal roles in protecting against bacterial, viral, and fungal infections in the intestine by fortifying the epithelial barrier via rapid secretion of soluble factors, such as IL-22, lymphotoxin α, and IL-17A, as well as regulating CD4+ T cell responses toward intestinal commensal bacteria (Fernandes et al., 2014, Gladiator et al., 2013, Hepworth et al., 2013, Hepworth et al., 2015, Kim et al., 2012, Klose et al., 2013, Satoh-Takayama et al., 2008). ILC3s are enriched in lymphoid tissues and at mucosal barrier surfaces, such as the intestinal tract, protecting against hazardous environmental stimuli together with other immune cells (Artis and Spits, 2015, Diefenbach et al., 2014, Eberl et al., 2015, Klose and Artis, 2016). Immune cells express various G-protein-coupled receptors (GPRs), including C-C motif chemokine receptors (CCRs), C-X-C motif chemokine receptors, and other GPRs, such as GPR183 and sphingosine-1-phosphate receptors, which regulate cell migration, accumulation, and distribution in tissues. Several chemokine receptors have been reported to control the accumulation of a subset of the ILC3s (Ivanov et al., 2006, Kim et al., 2015, Mackley et al., 2015, Satoh-Takayama et al., 2014); however, Maraviroc the molecular mechanisms that regulate the accumulation, distribution, and function of the entire ILC3 population in lymphoid and mucosal tissues and their effects on anti-bacterial responses and tissue protection are incompletely defined.