Calcium/Calmodulin‐Dependent Kinase IV Facilitates the Recruitment of Interleukin‐17–Producing Cells to Target Organs Through the CCR6/CCL20 Axis in Th17 Cell–Driven Inflammatory Diseases

Abstract

Objective The recruitment of IL-17-producing T helper (Th17) cells to inflammatory sites has been implicated in the development of organ damage in inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE). To define the mechanism of CaMK4 activation on Th17-cell recruitment to target tissues, we performed anti-glomerular basement membrane antibody-induced glomerulonephritis (AIGN) experiments in mice and studied samples from patients with SLE. Methods We induced experimental AIGN in Camk4-sufficient or -deficient mice and compared histology, Th17-related chemokine expression and numbers of IL-17-producing cells in the kidneys. We also evaluated the efficacy of the CaMK4 antagonist KN-93 in alter AIGN induced kidney disease. The expression of CCR6 in memory CD4 T cells before AIGN induction was analyzed by flow cytometry. We investigated the correlation between CCR6 expression in the peripheral blood and the severity of glomerulonephritis in patients with SLE. Results Camk4-deficient mice displayed less glomerular injury after the induction of AIGN. Kidney infiltration by IL-17-producing CD4 T cells along with CCR6 and CCL20 expression were significantly decreased in Camk4-deficient mice. Similarly, the KN-93 treatment of mice prior to exposure to AIGN improved the clinical and pathological finings. The expression and function of CCR6 in memory CD4 T cells in the peripheral blood was decreased in the Camk4-deficient mice. The expression of CCR6 correlated positively with the severity of organ damage in SLE patients. Conclusion Our results indicate that CaMK4 represents a novel therapeutic strategy for the treatment of Th17 cell-mediated tissue damage in inflammatory diseases.

Elevated levels of CCR6+ T helper 22 cells correlate with skin and renal impairment in systemic lupus erythematosus

“…It has been shown previously that expression of CCR6 on T effector cells positively correlates with the severity of organ impairment in SLE patients 33 , and CCR6/CCL20 axis aids in recruitment of IL-17 producing cells into targeted tissue, and, thus, results in tissue injury 24 , 33 . To validate these findings and have further clarify the mechanism of CCR6 + Th cells in the SLE organ impairment, we stratified SLE patients in our study into different subgroups (SK, SS, KS and NSK) based on skin and renal impairment.…”

CCR6+ Th cell distribution differentiates systemic lupus erythematosus patients based on anti-dsDNA antibody status

“…A significant association between CCR6 gene polymorphism and susceptibility to LN in SLE patients has also been reported ( Zhou et al, 2015 ). Furthermore, it has been identified that CCR6 chemokine expressed by the effector/memory CD4 + T cells plays a role tissue damage in SLE patients, including LN or neuropsychiatric SLE patients, and probably functions through CCR6/CCL20 axis at the inflamed sites ( Koga et al, 2016 ). These observations tentatively indicate that CCR6 + Th cells might be engaged in the aggravation of inflammatory reactions, and thus contributes to worse disease outcomes in anti-DNA + SLE patients.…”

“…In addition, cytokines expressed by T cells, including TNF- α and IL-17, both of which play an active role in autoimmunity, are increased in SLE patients ( Vincent et al, 2013 ). Moreover, the chemokine receptor, CCR6, expressed on Th cells, has been implicated in mediating the recruitment of IL-17 producing cells in glomerulonephritis ( Koga et al, 2016 ; Turner et al, 2010 ).…”

CC chemokine receptor 6 (CCR6) in the pathogenesis of systemic lupus erythematosus

“…In a murine model, blockade of T H 17 cell differentiation led to an amelioration of experimentally induced nephritis and reduction of infiltrating T H 17 cells. 57 Correspondingly, there was a decrease in Il17a, Ccr6 and Ccl20 mRNA expression in the kidneys of these mice relative to control mice. 57 Similarly, Yang et al 58 demonstrated that when a T H 17 cell-inhibiting compound derived from a herb (Baicalin) was administered to lupus-prone mice, the mice had a marked reduction in glomerulonephritis as assessed by histology and urine protein.…”

“…57 Correspondingly, there was a decrease in Il17a, Ccr6 and Ccl20 mRNA expression in the kidneys of these mice relative to control mice. 57 Similarly, Yang et al 58 demonstrated that when a T H 17 cell-inhibiting compound derived from a herb (Baicalin) was administered to lupus-prone mice, the mice had a marked reduction in glomerulonephritis as assessed by histology and urine protein. The treated mice also had a reduction in infiltrating T H 17 cells and a corresponding reduction in Ccl20 in kidneys compared with vehicle control-administered mice.…”