Calcium/Calmodulin Kinase IV Controls the Function of Both T Cells and Kidney Resident Cells

Andrew P Ferretti,Shani Dahan,Rhea Bhargava,George C Tsokos,Maria G Tsokos

doi:10.3389/fimmu.2018.02113

Andrew P Ferretti, Shani Dahan + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2018.02113

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Abstract

Calcium calmodulin kinase IV (CaMK4) regulates multiple processes that significantly contribute to the lupus-related pathology by controlling the production of IL-2 and IL-17 by T cells, the proliferation of mesangial cells, and the function and structure of podocytes. CaMK4 is also upregulated in podocytes from patients with focal segmental glomerulosclerosis (FSGS). In both immune and non-immune podocytopathies, CaMK4 disrupts the structure and function of podocytes. In lupus-prone mice, targeted delivery of a CaMK4 inhibitor to CD4+ T cells suppresses both autoimmunity and the development of nephritis. Targeted delivery though to podocytes averts the deposition of immune complexes without affecting autoimmunity in lupus-prone mice and averts pathology induced by adriamycin in normal mice. Therefore, targeted delivery of a CaMK4 inhibitor to podocytes holds high therapeutic promise for both immune (lupus nephritis) and non-immune (FSGS) podocytopathies.

Highlights

Calcium/calmodulin-dependent kinase IV (CaMK4) is a serine threonine kinase important for activating transcription factors downstream of T cell receptor (TCR) signaling
Aberrant activation of CaMK4 contributes to T cell abnormalities in systemic lupus erythematosus (SLE), a chronic systemic autoimmune disease presenting with diverse clinical manifestations [1]
cyclic-AMP response element modulator α (CREMα) recruits DNMT3a and HDAC1 which promote hypermethylation and silencing of gene transcription [25, 26]. This mechanism likely contributes to reduced levels of IL-2 in patients with SLE because deletion of CaMK4 reduces pCREMα binding to the IL-2 promoter, restores production of IL-2, and improves in vitro polarization of Treg cells

Summary

Introduction

Calcium/calmodulin-dependent kinase IV (CaMK4) is a serine threonine kinase important for activating transcription factors downstream of T cell receptor (TCR) signaling. Many studies suggest that CaMK4 is a central molecule contributing to multiple pathological pathways in T cells from patients with SLE including suppression of IL-2, increased production of IL-17, and imbalance between regulatory and Th17 cells. This mechanism likely contributes to reduced levels of IL-2 in patients with SLE because deletion of CaMK4 reduces pCREMα binding to the IL-2 promoter, restores production of IL-2, and improves in vitro polarization of Treg cells.

Results

Conclusion