TAKEDA Kiyoshi ≪Immune Regulation≫ “Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia”

PublishNature(2016) doi:10.1038/nature17406

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Inflammatory bowel diseases (IBD), such as ulcerative colitis (UC), are intractable diseases with unknown etiology. The number of patients with IBD in Japan has tremendously increased in late years. However, there are no definitive treatments at present. Recently, the dysfunction of intestinal mucosal barrier has been thought to be one of causes for IBD. Indeed, in genetically-modified mice in which the mucosal barrier is defective, intestinal bacteria invade the colonic mucosa and this causes high susceptibility to intestinal inflammation. Thus, it is important to understand how the mucosal barrier is formed for the elucidation of pathogenesis of IBD and development of effective therapy for IBD. In the colon where a tremendous number of bacteria exist, colonic epithelial cells are surrounded by the thick mucus and thereby protected from intestinal bacteria. However, the mechanism by which the mucus layer in the colon inhibits bacterial invasion has been unclear.
To address this issue, we focused on a gene named Ly6/Plaur domain containing 8 (Lypd8), which is highly and selectively expressed in colonic epithelial cells. We found that Lypd8 is a highly glycosylated GPI-anchored protein, and shed into the intestinal lumen. Human LYPD8 is also expressed in the colonic epithelia. We found that LYPD8 expression decreases in the colon of UC patients. In Lypd8-deficient mice, many intestinal bacteria invaded the inner mucus layer. Flagellated bacteria such as Proteus and Escherichia especially invaded the colonic mucosa in Lypd8-deficient mice. Many flagellated bacteria are known to be pathobionts implicated in the intestinal inflammation. Therefore, we analyzed the sensitivity to dextran sulfate sodium (DSS)-induced intestinal inflammation in Lypd8-deficient mice. Lypd8-deficient mice showed severe DSS-induced colitis compared to wild-type mice. Lypd8 bound to flagella of bacteria. In addition, Lypd8 inhibited the motility of bacteria in semisolid agar plate.
Our study demonstrates that Lypd8 highly expressed in the colonic epithelia is constitutively shed into the intestinal lumen and inhibits bacterial invasion of colonic epithelia by binding flagella and suppressing the motility of flagellated bacteria. Thorough this mechanism, Lypd8 regulates the intestinal homeostasis.