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  • Environmental cues such as microbial dietary and

    2021-06-17

    Environmental cues, such as microbial, dietary, and neuronal signals, regulate the differentiation and function of ILC3s. However, the identities of any additional cues and the receptors that detect them remain unknown. An important class of proteins enabling cells to sense extracellular cues are G-protein-coupled receptors (GPCRs), which mediate cellular responses to diverse environmental signals. We therefore hypothesized that ILC3 function is regulated by GPCRs that recognize endogenous metabolites. In this regard, we focused on G-protein-coupled receptor 183 (GPR183, also known as EBI2), a GPCR that instructs antibody (Ab) responses in lymphoid organs through the positioning of B cells, T cells, and DCs (Gatto et al., 2009, Gatto et al., 2013, Li et al., 2016, Pereira et al., 2009, Yi and Cyster, 2013). GPR183 is a receptor for oxysterols (Hannedouche et al., 2011, Liu et al., 2011), hydroxylated metabolites of cholesterol, which have pleiotropic roles in lipid metabolism, immunity, and inflammation (Cyster et al., 2014). The most potent GPR183 ligand is 7α,25-hydroxycholesterol (7α,25-OHC). Synthesizing 7α,25-OHC from cholesterol requires the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450, family 7, subfamily b, polypeptide 1 (CYP7B1), whereas hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7 (HSD3B7) metabolizes 7α,25-OHC into bile 5-(N,N-dimethyl)-Amiloride hydrochloride precursors that lack GPR183 ligand activity. Given that GPR183 regulates immune cell migration, we reasoned that oxysterols could function as guidance cues for ILC3s. Here, we report that ILC3s sensed oxysterols through GPR183, which was highly expressed by LTi-like ILC3s. 7α,25-OHC-synthesizing enzymes were produced by fibroblastic stromal cells found in intestinal lymphoid structures, and the GPR183 ligand 7α,25-OHC acted as a chemoattractant for ILC3s. GPR183 and 7α,25-OHC were required for ILC3 localization to lymphoid structures in the colon, and ablation of Gpr183 in ILC3s caused a defect in the formation of colonic CPs and ILFs. The same phenotype was observed in mice lacking Ch25h, demonstrating a requirement for oxysterols in lymphoid tissue organogenesis. Furthermore, 7α,25-OHC was increased by inflammatory signals, and GPR183 controlled inflammatory cell recruitment during colitis. Consequently, Gpr183-deficient mice were less susceptible to colitis in an innate model of intestinal inflammation. Our results establish a role for a lipid ligand and its cell-surface receptor in controlling ILC3 migration, lymphoid tissue development, and inflammatory responses in the intestine.
    Results
    Discussion Little is known regarding how ILCs directly sense signals from their environment and which signaling pathways enable ILCs to perform tissue remodeling. Our work demonstrates that LTi-like ILC3s were controlled by oxysterols that signal through the receptor GPR183. This instructs ILC3 positioning and lymphoid tissue formation in the colon. We propose a model where local generation of 7α,25-OHC by fibroblastic stromal cells attracts GPR183-expressing LTi-like ILC3s to sites of CP formation. This process positions LTα1β2+ ILC3s for crosstalk with LTβR+ stromal cells, which promotes the recruitment of GPR183-expressing B cells, to complete ILF formation. Moreover, our study provides information on the mechanisms that control the spatial and functional compartmentalization of ILC3s in the intestine. After homing to the intestine, ILC3s segregate into two distinct locations. Localization of NKp46+ ILC3s to the villi of the lamina propria occurs in a CXCL16-CXCR6-dependent manner, which supports epithelial defense through the production of IL-22 (Satoh-Takayama et al., 2014). We have shown that GPR183 and its ligand 7α,25-OHC position LTi-like ILC3s to colonic CPs, where these cells promote lymphoid tissue formation. Previous studies have established an essential function for GPR183 and its ligand 7α,25-OHC in lymphoid organs and humoral immunity (Gatto et al., 2009, Gatto et al., 2013, Hannedouche et al., 2011, Li et al., 2016, Liu et al., 2011, Pereira et al., 2009, Yi and Cyster, 2013, Yi et al., 2012). We have now demonstrated a role for GPR183 and oxysterols in lymphoid tissue development in the large intestine. Thus, our study has established a broader function of the oxysterol-GPR183-ligand-receptor system by linking GPR183-mediated cell positioning to tissue reorganization during steady-state homeostasis and inflammation. Whereas the signals regulating the formation of SILTs in the small intestine are well known, those in the colon have remained poorly understood. As in the small intestine, LTi-like ILC3s and LTα1β2 are required for colonic lymphoid organogenesis. However, the microbiota and receptor activator of NF-κB ligand (RANKL)-RANK, CXCL13-CXCR5, and CCL20-CCR6 are required for ILF development only in the small intestine (Buettner and Lochner, 2016, Randall and Mebius, 2014). Accordingly, we have described a colon-specific pathway governing the postnatal development of lymphoid tissues.