The role of indoxyl sulfate, a circulating uremic toxin, for inflammatory responses in the patients with end-stage renal disease

Abstract

Progressive reduction in renal function causes uremia-related immune dysfunction featuring a chronic ¬inflammatory milieu and a concomitantly impaired immune system. In the patients with end-stage renal disease (ESRD), a major cause of death is cardiovascular disease (CVD) and its pathologic processes have been suggested to closely link to uremia-related chronic inflammation. Although accumulating evidence suggests a pivotal role of ESRD-related immune dysfunction for pathogenesis of cardiovascular diseases, little is known about how uremic toxins affect cellular immune systems involved with chronic inflammatory responses and what is a contribution of these immune changes for development and progression of atherosclerotic disease in the ESRD patients. Thus, I investigated phenotypic and functional characteristics of circulating CD4+ T cells and monocytes in the patients with ESRD and their immune responses mediated by indoxyl sulfate (IS), a key uremic toxin in order to explore the pathogenic roles of these cells for vascular endothelial cells. In ESRD patients, CD4+CD28null T cells and unconventional CD16+ monocytes, including both CD14+CD16+ and CD14dimCD16+ subsets, were predominantly expanded in peripheral blood when compared with age-matched HCs. Global transcriptome analyses clearly demonstrated that monocytes of ESRD patients had a typical inflammatory gene signature. To explore how uremic milieu influences immune responses, monocyte were stimulated with IS in the absence or presence of LPS. Monocytes responded to IS through aryl hydrocarbon receptor (AhR) and consequently produced significantly enhanced amount of proinflammatory cytokines such as TNF-α. Upon stimulation with TNF-α, human vascular endothelial cells predominantly produced CX3CL1, a specific chemokine ligand of CX3CR1 which is markedly overexpressed by CD4+CD28null T cells and CD16+ monocytes. Migration assay revealed that CD4+CD28null T cells are preferentially recruited by CX3CL1. Moreover, CD4+CD28null T cells have cytotoxic capability which allowed for induced apoptosis of human vascular endothelial cells in response to TCR stimulation. My findings suggest that IS-mediated immune dysfunction may play a critical role for development and accelerated progression of CVD through vascular endothelial cell damage in the ESRD patients.