Essential role of epithelial TRAF6 in the determination of Th17 polarization

Epithelial tissues not just provide a physical barrier but shape the host immune response in part by epithelial-immune relationship at frontline. Indeed, it has been demonstrated that epithelial cells release a number of mediators that affect the function and kinetics of immune cells in several types of immune response. However, a specific cellular machinery in epithelial cells, whose activation is essential for the decision of the type of immune response, remains elusive. Here, we sought to assess the impact of deficiency of a specific signalling molecule in keratinocytes under several stimulations. Tumor necrosis factor receptor associated factor 6 (TRAF6) is an adopter protein which is essential for the activation of NF-kappaB and MAPK pathway. We genetically deleted TRAF6 specifically in keratinocytes of animals (K5-TRAF6 KO mice), and induced Th1-type dermatitis by DNFB contact hypersensitivity or Th2-type dermatitis by papain occlusive dressing technique. In the both situations, no significant differences were found between the control and K5-TRAF6 KO mice. However, K5-TRAF6 KO mice were totally protected from Th17-type psoriasis-like dermatitis induced by topical imiquimod treatment, and the activation of dendritic cells and the induction of IL-17-producing T cells were defective. Furthermore, intracutaneous injection with IL-23 fully reconstituted the expression of IL-17 and IL-22 in the KO mice, showing that IL-23 is a major downstream effector of the epidermal TRAF6. Moreover, defective response of TRAF6-null keratinocytes to IL-17 suggested a further role of the TRAF6 in an IL-17-mediated inflammatory loop. Taken together, our findings strongly suggest that a TRAF6-dependent machinery in epithelial cells is essential to organize Th17-mediated inflammation.