Gpr37 contributes to inflammation-induced GI dysmotility by regulating enteric reactive gliosis.

The enteric nervous system (ENS) is contained within two layers of the gut wall and is made up of neurons, immune cells, and enteric glia cells (EGCs) that regulate gastrointestinal (GI) function. EGCs in both inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) change in response to inflammation, referred to as reactive gliosis. Whether EGCs restricted to a specific layer or region within the GI tract alone can influence intestinal immune response is unknown. Using bulk RNA-sequencing and in situ hybridization, we identify G-protein coupled receptor, Gpr37, as a gene expressed only in EGCs of the myenteric plexus, one of the two layers of the ENS. We show that Gpr37 contributes to key components of LPS-induced reactive gliosis including activation of NF-kB and IFN-y signaling and response genes, lymphocyte recruitment, and inflammation-induced GI dysmotility. Targeting Gpr37 in EGCs presents a potential avenue for modifying inflammatory processes in the ENS. Overall design: Transcriptional profiles of EGCs from: (1) all four regions and layers of the GI tract in adult Plp1eGFP mice, n= 5-6. (2) LPS- or PBS-treated Plp1eGFP mice in the SI MP and colon MP, n=4, 2-hour timepoint. (3) LPS- or PBS-treated Gpr37WT; Plp1eGFP and Gpr37-/-; Plp1eGFP mice in the SI MP and colon MP, n=4-6, 24-hour timepoint.