Myeloid Cell Adhesion Molecule 1 (CADM1) Promotes Proinflammatory Signaling in Human Inflammatory Bowel Diseases

Abstract

Background & aims: Cytotoxic T cells have been postulated to facilitate the destruction of intestinal epithelium in inflammatory bowel diseases (IBDs). CADM1, which encodes a membrane adhesion protein that can bind the T cell receptor CRTAM, was markedly up regulated in colons of IBD patients compared with non-IBD (NIBD) patients.

Methods: We performed comprehensive small RNA and RNA profiling on colon tissue from IBD and NIBD control patients in addition to characterizing the serum cleaved ectodomain of CADM1 (sCADM1) function in lamina propria mononuclear cells isolated from these patients. Last, a conditional loss-of-function mouse was developed to assess Cadm1 function in the myeloid compartment during chemical-induced colitis.

Results: We identified CADM1 enrichment in multiple immune cell clusters including macrophages and dendritic cells in the colons of IBD patients. Increased numbers of CADM1⁺ myeloid cells were measured adjacent to CD8⁺ T cells within colons of ulcerative colitis patients compared with NIBD patients. Conditional deletion of Cadm1 in myeloid cells resulted in reduced numbers of activated T cell populations and protected mice from chemical-induced colitis. Similarly, administration of a Cadm1 "neutralizing" antibody, which binds its extracellular domain reduced tissue inflammation and breakdown of the intestinal epithelium and crypts after induction of colitis in mice. Last, serum levels of sCADM1 were elevated in IBD patients compared with NIBD control subjects and treatment of lamina propria mononuclear cells with recombinant sCADM1 enhanced inflammatory STAT3 phosphorylation.

Conclusions: CADM1 is a mediator of proinflammatory signaling cascades in the colon and a potential therapeutic target for the IBDs.

Keywords: CADM1; Cytotoxic T Lymphocytes; Myeloid; Ulcerative Colitis.