IDDF2021-ABS-0061 TM9SF4 ameliorates inflammatory bowel disease by alleviating inflammation and er stress in colonic epithelial cells and macrophages

Abstract

<h3>Background</h3> Inflammatory bowel disease (IBD) is a result of excess inflammation and inappropriate immune response to environmental changes and the gut microbiota. The search of genome-wide association study (GWAS) database identified a remarkable correlation between TM9SF4 gene and IBD, with p-value = 6×10¹⁰. In the previous studies, TM9SF4 was found to be highly expressed in macrophages and intestinal epithelial cells (IECs), promoting phagocytosis and innate immune response. Besides, TM9SF4 reduced cell stress to protect cells from apoptotic deaths. Therefore, it is likely that TM9SF4 might exert protective roles in IBD via its actions of reducing inflammation and alleviating ER stress in both macrophages and IECs. <h3>Methods</h3> Expression levels of TM9SF4 were compared between actively inflamed and non-inflamed regions of colons from IBD patients by immunohistochemistry and western blotting. Dextran sulfate sodium (DSS)-induced colitis was established in wild-type (WT) and TM9SF4 knockout (KO) mice. Bone marrow transplantation was used to elucidate the contribution of myeloid cells and IECs in disease progression. Intestinal permeability, IECs stress and deaths, macrophage phagocytosis functions and polarization were measured with in vitro and in vivo techniques. <h3>Results</h3> Decreased expression of TM9SF4 was observed in inflamed regions of colon tissues from patients with IBD. Patients with a higher Mayo score showed lower expression of TM9SF4 in their colons. In animal studies, knockout of TM9SF4 aggravated DSS-induced colitis, which could be attributed to TM9SF4 deficiency in bone marrow-derived hematopoietic cells as well as in colonic epithelial cells. For IECs, loss of TM9SF4 impaired epithelial barrier functions by promoting inflammation, elevating ER stress, oxidative stress and consequently contributing to apoptotic deaths. For macrophages, more colonic infiltration of macrophages was observed in TM9SF4 KO mice than in WT mice. Besides, TM9SF4 facilitated clearance of apoptotic cells by colonic macrophages, enhanced monocytes polarization into proinflammatory M1 macrophages while suppressed M2 macrophages polarization in vitro and in vivo. <h3>Conclusions</h3> Our studies suggested that TM9SF4 in intestinal epithelial cells and macrophages may act in coordinated ways to exert its anti-inflammatory role in IBD.