IL-35+ regulatory immune cells in diabetic nephropathy

Abstract

Abstract Diabetes causes an elevation of the blood glucose level and a long-term hyperglycemia contributes to kidney damage, i.e. diabetic nephropathy (DN). DN exhibits signs of inflammation and infiltration of mononuclear cells in kidney. Regulatory T cells (Tregs), regulatory B cells (Bregs), tolerogenic antigen presenting cells (tolAPCs) maintain the homestasis of the immune system, specifically by producing anti-inflammatory cytokine IL-35. Despite intensive research the role of Tregs, Bregs and tol APCs and IL-35 is not yet clear. Herein, we investigated the role of these immune cells in mice and patients. The circulating concentration of IL-35 was lower in T1D patients with DN and without DN than healthy controls. Proportions of IL35+Treg, IL-35+Bregs, IL-35+tolAPCs were lower but IL-17+Tregs were higher in patients with DN compared to healthy controls, suggesting a phenotypic shift of Tregs. The proportions of IL35+Treg, IL-35+Bregs, IL-35+tolAPCs were lower in kidneys of diabetic mice. Furthermore, IFN-gamma+ Tregs were higher in kidneys of diabetic mice, indicating a phenotypic shift of Treg cells. After the administration of IL-35 in diabetic mice the mice became normoglycemic and had a lowered albumin creatinine ratio compared to control mice. The IL-IL35+Treg, IL-35+Bregs, IL-35+tolAPCs were increased in IL-35 treated mice. IFN-gamma+Tregs were decreased and the number of Foxp3+ cells was decreased, and mononuclear cells infiltration was also decreased in kidneys of IL-35 treated mice. Our data suggest that IL-35+ regulatory immune cells are impaired in DN and systemic administration of IL-35 prevents the development of DN in mouse models of DN.