GPR183 controls spatial organization and survival of hepatic conventional dendritic cells within hepatic portal regions via M-CSF and Gas6

Abstract

G protein-coupled receptor 183 (GPR183) recognizes 7α,25-dihydroxycholesterol (7α,25-OHC) and exerts chemotactic action upon recognition. Recent studies have shown that GPR183 is highly expressed in T, B and dendritic cells (DCs) and is essential for the correct positioning of splenic DCs within the marginal zones of spleen. Nevertheless, whether GPR183 plays a similar role in positioning and regulating DC homeostasis in the cholesterol-rich microenvironment of the murine liver remains elusive. Therefore, we set out to investigate the role of GPR183 on murine liver resident dendritic cells during homeostasis. <br /> To understand the role of GPR183 in hepatic DC maintenance, we analyzed the abundance and phenotype of liver resident DCs in WT, Gpr183^-/-, Gpr183^flox/flox-Zbtb46-cre⁺ Ch25h^-/-, Cyp7b1^-/- animals by means of high dimensional flow cytometry coupled to transcriptomics and spatial imaging analyses. <br /> Our data shows that lack of GPR183 resulted in increased abundance of hepatic cDC and DC progenitors due to their increased in-situ proliferation and impaired apoptosis. Next, we investigated whether an active production of 7α,25-OHC is needed to maintain normal DC numbers in the liver and we assessed the liver-resident DC compartment of Ch25h^-/- and Cyp7b1^-/- mice. Here we observed an increased abundance of hepatic DCs within these mice. <br /> Furthermore, analysis of chimeric experiments revealed that the radioresistant stromal compartment is crucial for maintaining the DC pool size and that DCs are closely associated with 7α,25-OHC producing endothelial cells in the portal regions of the liver. Next, our singlecell transcriptomics data and NIchenet-based in-silico receptor-ligand inference alongside spatial analyses identified M-CSF-M-CSFR and Gas6-Axl endothelial cell-DC interactions as crucial to the control of DC pool size within the murine liver. Additionally, blocking the gut-liver axis cholesterol transport also showed similar M-CSF and Gas6 dependent increase in hepatic DC numbers. Finally, to understand the role of GPR183 in disease and pathophysiological conditions we fed WT and Gpr183f^lox/flox-Zbtb46-cre⁺ animals on CDAAHFD and our data showed a significantly increased lipid content and decreased ALT and AST serum concentration in KO animals compared to their WT counterparts. <br /> Taken together, these findings demonstrate that GPR183 plays a cell-intrinsic role in organization and survival of hepatic DCs in murine liver. Additionally, M-CSF and Gas6 produced by endothelial cells in the portal regions act as the guiding niche factor for positioning and survival of cDCs within the portal regions of liver. Our data also shows possible implication of GPR183 in health and disease and could pave ways for developing novel therapeutic targets for liver diseases.