Loss of TGFβ signaling in dendritic cells leads to increased susceptibility to epithelial injury and deficient production of IL-22 and IL-17a by the innate immune cells

Selective loss of TGFβ signaling in dendritic cells (Tgfbr2^ΔDC, JI 2012,189:3878) leads to increased activation of T cells and autoimmunity. DCs interact with other innate immune cells to provide the first line of defense against infection and translocation of commensals during mucosal injury. The mechanisms that mediate this crosstalk are not clearly understood. Cre^- and Cre⁺ Tgfbr2^ΔDC mice on Rag2^-/- background (DKO) were evaluated for their susceptibility to 2% dextran sodium sulfate (DSS). Compared to DSS-treated Cre^- mice, DSS-treated Cre⁺ mice exhibited significantly more severe phenotype with accelerated and greater body weight loss. Histological analysis revealed severe inflammation and infiltration of the distal colon, extensive mucosal erosions cells and a complete loss of goblet cells. Despite the similar neutrophilic infiltration based on the H&E analysis, immunohistochemistry, and mucosal MMP8 mRNA expression, contrary to Cre^- DKO, Cre⁺ mice failed to upregulate IL-22 and IL-17a, cytokines implicated in mucosal protection during epithelial barrier breach. Although the exact mechanism and the type of innate immune cells affected are still under investigation, loss of TGFβ signaling in DCs as an initial steps in mucosal inflammation may lead to insufficient initial protective innate immune responses and contribute to the establishment of chronic disease.