Abstract
Diabetes mellitus is characterized by chronic inflammation and increased risk of infections, particularly of tissues exposed to the external environment. However, the causal molecular mechanisms that affect immune cells and their functions in diabetes are unclear. Here we show, by transcript and protein analyses, signatures of glucose-induced tissue damage, chronic inflammation, oxidative stress, and dysregulated expression of multiple inflammation- and immunity-related molecules in diabetic kidneys compared with non-diabetic controls. Abnormal signaling involving cytokines, G-protein coupled receptors, protein kinase C isoforms, mitogen-activated protein kinases, nuclear factor-κB (NFκB), and Toll-like receptors (TLR) were evident. These were accompanied by overexpression of negative regulators of NFκB, TLR, and other proinflammatory pathways, e.g., A20, SOCS1, IRAK-M, IκBα, Triad3A, Tollip, SIGIRR, and ST2L. Anti-inflammatory and immunomodulatory molecules, e.g., IL-10, IL-4, and TSLP that favor TH2 responses were strongly induced. These molecular indicators of immune dysfunction led us to detect the cryptic presence of bacteria and human cytomegalovirus in more than one third of kidneys of diabetic subjects but none in non-diabetic kidneys. Similar signaling abnormalities could be induced in primary human renal tubular epithelial (but not mesangial) cell cultures exposed to high glucose, proinflammatory cytokines and methylglyoxal, and were reversed by combined pharmacological treatment with an antioxidant and a PKC inhibitor. Our results suggest that diabetes impairs epithelial immunity as a consequence of chronic and inappropriate activation of counter-regulatory immune responses, which are otherwise physiological protective mechanisms against inflammation. The immune abnormalities and cryptic renal infections described here may contribute to progression of diabetic nephropathy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-012-0969-x) contains supplementary material, which is available to authorized users.
Highlights
Many studies have shown infection to be a major cause of death among diabetics [1,2,3,4,5]
Abnormalities of innate immunity mediated by leukocytes, macrophages, natural killer, and dendritic cells have been observed in diabetes [7,8,9]
Our results suggest that diabetes and hyperglycemia per se impair renal epithelial immunity as a consequence of inappropriately activated negative counter-regulatory responses, which are physiological protective mechanisms against chronic inflammation
Summary
Many studies have shown infection to be a major cause of death among diabetics [1,2,3,4,5]. Abnormalities of innate immunity mediated by leukocytes, macrophages, natural killer, and dendritic cells have been observed in diabetes [7,8,9]. Disordered cell-mediated immunity in diabetes is reflected in reduced leukocyte adherence, chemotaxis and phagocytosis, impaired oxidative burst and intracellular bactericidal activities, and diminished production of antimicrobial cytokines [7, 10,11,12,13]. Diabetes impairs adaptive immunity via the cell-mediated arm [14, 15] and humoral immunity [7]. Despite evidence of diverse alterations of immune function in vitro, their relevance to the risk of infections among diabetic patients in vivo is controversial [16,17,18]. Indubitable evidence correlates good glycemic control with improved immune function and lower infection rates [1, 14, 19]
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