TRAF5-deficiency in non-hematopoietic cells ameliorates acute intestinal inflammation

概要

TNF receptor (TNFR) associated factor (TRAF) 5 is a signaling adaptor molecule for TNF receptor superfamily that plays important roles in immune cells, such as lymphocytes and macrophages. However, physiological functions of TRAF5 in non-hematopoietic cells such as intestinal epithelial cells (IECs), especially in inflammatory responses, are not well understood. Here, I found that after a short course of colitogenic dextran sulfate sodium (DSS) administration, Traf5-/- IECs showed a transient reduced expression of TRAF2 protein, a signaling adaptor for TNF/TNFR1/NF-κB signaling, and a significant decrease in NF-κB-related inflammatory gene expression (Tnf, Il6 and Cxcl1). In line with that, a more resistant intestinal barrier and a more attenuated severity to DSS exposure were seen in Traf5-/- mice or irradiated Traf5-/- recipient mice that reconstituted with wild-type bone marrow as compared to their control mice. Furthermore, data from in vitro experiments with non-hematopoietic mouse embryonic fibroblast harvested from wild-type and Traf5-/- mice implicated a role of TRAF5 in negatively regulating TNF receptor II (TNFR2)-mediated proteasome-dependent degradation of TRAF2 in an inflammatory condition. Thus, my study demonstrates that IEC-intrinsic TRAF5 may play a pathogenic role in DSS-induced colitis via promoting TRAF2-mediated NF-κB signaling.