Role of E-Cadherin of Dendritic Cells in Colonic Homeostasis

BACKGROUND: TGF-β has been reported to limit E-cadherin expression of dendritic cells (DCs). Here we investigated the role of DC's E-cadherin in colonic homeostasis associated with TGF-β signaling and microbial communities.METHODS: We used mice with DC-specific deletion of TGF-β signaling (CD11c-Cre Tgfbr2^fl/fl) and E-cadherin (CD11c-Cre Cdh1^fl/fl). Fecal DNA from CD11c-Cre Tgfbr2^fl/fl and Cre-negative control mice was used for 16S rRNA next-generation pyrosequencing analysis. E-cadherin expression was analyzed by flow cytometry, qPCR, and immunoblotting. To analyze the effect of TGF-β signaling on E-cadherin expression, we examined E-cadherin expression of BMDCs with in vivo deletion of TGF-β signaling using Cre-expressing-adenoviral and Tgfbr2-shRNA-lentiviral approaches. CD11c-Cre Cdh1^fl/fl and control mice were treated with dextran-sulfate-sodium (DSS).RESULTS: CD11c-Cre Tgfbr2^fl/fl mice showed spontaneous colitis with enhanced E-cadherin expression in intestinal DCs. In vitro, E-cadherin expression of BMDCs was also upregulated by inhibiting TGF-β signaling. Principal-component analysis of 16S rRNA transcripts showed that marked separation of microbial composition between CD11c-Cre Tgfbr2^fl/fl and control mice. In family-level analysis of 16S rRNA pyrosequencing, the expansion of Enterobacteriaceae was the most significant change in CD11c-Cre Tgfbr2^fl/fl microbial communities. CD11c-Cre Cdh1^fl/fl mice treated with DSS exhibited significantly attenuated the sign of colitis compare with controls, suggesting E-cadherin⁺ DCs are proinflammatory.CONCLUSIONS: E-cadherin expression and TGF-β signal loss of DCs are associated with the development of dysbiosis and colitis. Blocking of DC's E-cadherin may have therapeutic potential for IBD.