Myeloid Cell Adhesion Molecule 1 (CADM1) promotes pro-inflammatory signaling during Inflammatory Bowel Disease.
Background and aims: Cytotoxic T cells have long been postulated to facilitate autoimmune destruction of intestinal epithelium; and the precise causal events leading to inflammatory bowel diseases (IBDs) remain unresolved. CADM1, a membrane adhesion protein which can shed its extracellular ectodomain enters the systemic circulation as well as bind the receptor CRTAM present on CD8+ T cells. Methods: We performed RNA and small RNA sequencing on colon tissue from IBD and non-IBD (NIBD) control patients. We performed spatial transcriptomics and stimulated lamina propria mononuclear cells (LPMCs) with the soluble form of CADM (sCADM1) in these patients. Dextran Sulfate Sodium (DSS) was used to induced colitis in a conditional myeloid Cadm1 loss-of-function mouse. Results: MicroRNA-375 was significantly decreased while its direct target CADM1 was markedly up-regulated in UC patients compared to NIBD control subjects. Single cell proteomics data identified CADM1 enrichment in multiple clusters including macrophages and dendritic cells from colonic tissue of human subjects with IBD. An increased number of CADM1+CD68+ cells was detected adjacent to CD8+ T-cells within the intestinal epithelium of colon sections from patients with ulcerative colitis (UC) compared to NIBD subjects. Myeloid Cadm1 conditional knockout mice were protected against DSS-induced colitis indicating Cadm1 may facilitate binding/localization of cytotoxic cell populations within the gut epithelium. Furthermore, we observed that serum levels of the cleaved extracellular ectodomain of CADM1 (sCADM1) are elevated in medically refractory UC patients compared to non-IBD and UC donors in remission and treatment of LPMCs with recombinant sCADM1 enhanced STAT3 phosphorylation. Conclusions: Together these results identify CADM1 as a potent mediator of pro-inflammatory signaling pathways and demonstrate its potential as a diagnostic and therapeutic target for preventing the IBDs. Overall design: We performed small RNA sequencing on colon tissue from IBD and non-IBD (NIBD) control patients.