Molecular Medicine 2014

Expression of Blimp-1 in Dendritic Cells Modulates the Innate Inflammatory Response in Dextran Sodium Sulfate–Induced Colitis

Sun Jung Kim, Jordan Goldstein, Kimberly Dorso, Miriam Merad, Lloyd Mayer, James M Crawford, Peter K Gregersen, and Betty Diamond

A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease.Here, we demonstrate that Blimp-1 in CD103+ dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1cko mice with a deletion of Blimp-1 in CD103+ DCs and CD11chi macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103+ DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1cko mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow–derived DCs from Blimp-1cko produced increased matrix metalloproteinases in an interleukin (IL)-1β– and IL-6–dependent manner. Treatment of Blimp-1cko mice with anti–IL-1β and anti–IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease.

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Posted by Sheila Platt on Mar 24, 2015 1:42 PM CDT