Background IL-17 producing T helper (Th17) cells have been closely associated with the development of organ damage in inflammatory and autoimmune diseases. We have previously reported that Calcium/calmodulin-dependent protein kinase IV (CaMK4) plays a crucial role in Th17 cell differentiation invitro and invivo and suggested that CaMK4 inhibition ameliorates clinical and pathological findings in experimental autoimmune encephalomyelitis (EAE) and MRL/lpr mice (1). We have also shown that Il-17 is important in the expression of anti-glomerular basement membrane Ab-induced glomerulonephritis (AIGN) (2). However, the effect of CaMK4 on recruitment of pathogenic T cells to target tissues in inflammatory settings has not been studied.
Objectives The aim of this study is to determine the role of CaMK4 in the infiltration of inflammatory cells to target tissues and to explore its mechanism.
Methods We induced experimental AIGN in Camk4 sufficient or deficient mice and compared the kidney injury including the number of IL-17 producing cells and the expression of CCR6 and CCL20 in both groups. We also evaluated the effect of KN-93, a compound of CaMK4 antagonist in this AIGN model.
Results Camk4 deficient mice displayed less glomerular injury and less proteinuria at day 14 and at day 21 after induction of AIGN. The expression of CCR6 and CCL20 in inflamed kidney is lower in Camk4 deficient mice. Kidney infiltration by Th17 producing CD4+ T cells was decreased significantly in Camk4 deficient mice, suggesting that CaMK4 facilitated AIGN damage by promoting local inflammatory cells accumulation. In line with these observations, KN-93 treatment improved clinical and pathological finings in mice induced AIGN at dose dependent manner.
Conclusions Collectively, our results indicate that CaMK4 inhibition might be a novel therapeutic strategy of Th17 cells-mediated inflammatory diseases.
CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. Koga T, Hedrich CM, Mizui M, Yoshida N, Otomo K, Lieberman LA, Rauen T, Crispín JC, Tsokos GC. J Clin Invest. 2014 May 1;124(5):2234-45.
Cutting edge: protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism.Crispín JC, Apostolidis SA, Rosetti F, Keszei M, Wang N, Terhorst C, Mayadas TN, Tsokos GC.J Immunol. 2012 Apr 15;188(8):3567-71.
Disclosure of Interest None declared