NDR1 Protein Kinase Positively Regulates IL-17-mediated Inflammation

Interleukin 17(IL-17A or IL-17)has been recognized as a pro-inflammatory cytokine mainly produced by Th17 cells.IL-17 plays an important role in anti-infection immunity,and it is responsible for the development of many autoimmune diseases,such as multiple sclerosis,inflammatory bowel disease and psoriasis.However how it signals is not well understood.Here we found that silencing of NDR1 inhibits IL-17-induced expression and production of chemokines and cytokines,whereas overexpression of NDR1 and its kinase dead mutant promotes IL-17-induced pro-inflammatory molecules.Consistent with that,IL-17-triggered the expression of pro-inflammatory genes were decreased in NDR1 deficient MEF and primary astrocyte cells compared with the wild-type MEF and primary astrocyte cells.Ndr1-/-mice showed less sensitivity to IL-17-induced peritonitis.Consistently,mice deficient in NDR1 were largely protected from myelin oligodendrocyte glycoprotein(MOG)-induced experimental autoimmune encephalomyelitis(EAE).In addition,Ndr1-/-mice showed more resistant in 2,4,6-trinitrobenzenesulfonic acid(TNBS)-induced colitis.The expression of NDR1 was significantly increased in the colon tissue from patients with colitis compared with the normal tissue.Mechanistically,silencing of NDR1 inhibits the activation of ERK1/2,p38 and NF-κB in Hela cells.NDR1 deficiency also inhibits the activation of ERK1/2,p38 and NF-κB in MEF and primary astrocyte cells.We next found that NDR1 binded to TRAF3 directly and prevents its binding to IL-17R,which promoted formation of IL-17R-Act1-TRAF6 complex and downstream signaling.Thus,we identify that NDR1 positively regulates IL-17-induced inflammation.The present information from cell culture,animal studies suggest that NDR1 is a positive regulator in IL-17-triggered inflammation,and NDR1 expression is increased in the colons of ulcerative colitis(UC)patients.Taken together,NDR1 may be a potential therapeutic target for the IL-17-dependent infection and autoimmune inflammatory diseases.