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  • One question relates to our finding that oxysterol GPR


    One question relates to our finding that oxysterol-GPR183 signaling is critical for CP and ILF formation in the colon but dispensable in the small intestine. GPR183 and its ligand were expressed in both the small and large intestines. Moreover, 7α,25-OHC was required for ILC3 migration to CPs not only in the colon but also in the small intestine. Despite this, lymphoid tissue development in the small intestine was normal in mice lacking 7α,25-OHC. Together, our observations indicate that, as a compensatory response, GW 6471 receptor form lymphoid follicles when ILC3s are unable to migrate to CPs as a result of a lack of GPR183 ligand. This notion is supported by previous studies demonstrating lymphoid-tissue-inducing activity of B cells and compensatory lymphoid tissue formation when ILC3s are absent or when LTβR signaling is blocked in utero (Buettner and Lochner, 2016). This process must be driven by factors that operate specifically in the small intestine, because we observed compensatory B cell cluster formation only in the small intestine, but not in the colon. Such factors are the microbiota, CCL20, and CXCL13, which are all dispensable for ILC3 recruitment and CP formation but essential for B cell recruitment and ILF formation in the small intestine (Buettner and Lochner, 2016). In conclusion, we favor the concept that the 7α,25-OHC-GPR183 pathway is active, but not absolutely required for lymphoid tissue formation, in the small intestine because other redundant factors are sufficient in the absence of GPR183 ligand. 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 aggregates 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.
    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.