Increased Atherosclerotic Lesion Formation and Vascular Leukocyte Accumulation in Renal Impairment Are Mediated by Interleukin-17A

Abstract

Rationale Atherosclerosis is a major cause of death in patients with chronic kidney disease. Chronic inflammation of the arterial wall including invasion, proliferation and differentiation of leukocytes is important in atherosclerotic lesion development. How atherosclerotic inflammation is altered in renal impairment is incompletely understood. Objective This study analyzed leukocytes of the atherosclerotic aorta in mice with impaired and normal renal function and studied a mechanism for the alteration in aortic myeloid leukocytes. Methods and Results Unilateral nephrectomy significantly decreased glomerular filtration rate and increased atherosclerotic lesion size and aortic leukocyte numbers in two murine atherosclerosis models, Apolipoprotein E (Apoe−/−) and LDL receptor (LDLr−/−) deficient mice. The number of aortic myeloid cells increased significantly. They took up less oxidized LDL, while CD11c expression, interaction with T cells and aortic T cell proliferation were significantly enhanced in renal impairment. In human PBMC cultures, chronic kidney disease serum decreased lipid uptake and increased HLAII expression. Supplementation with Interleukin (IL)-17A similarly increased HLAII and CD11c expression and impaired oxLDL uptake. IL-17A expression was increased in atherosclerotic mice with renal impairment. Ablation of IL-17A in LDLr−/− mice by lethal irradiation and reconstitution with Il17a−/− bone marrow abolished the effect of renal impairment on aortic CD11b+ myeloid cell accumulation, CD11c expression and cell proliferation. Atherosclerotic lesion size was decreased to levels observed in normal kidney function. Conclusions Kidney function modifies arterial myeloid cell accumulation and phenotype in atherosclerosis. Our results suggest a central role for IL-17A in aggravation of vascular inflammation and atherosclerosis in renal impairment.

T Cell CX3CR1 Mediates Excess Atherosclerotic Inflammation in Renal Impairment

“…[4][5][6] Renal impairment increased atherosclerotic aortic lesions as previously described ( Figure 1A, clinical characteristics in Supplemental Table 1). [4][5][6][7] Absence of CX3CR1 (CX3CR1 gfp/gfp , termed CX3CR1 2/2 throughout this manuscript) impeded atherosclerosis development as previously reported.…”

“…[1][2][3] Unilateral nephrectomy significantly decreases renal function in Apoe 2/2 and LDL receptor (LDLr 2/2 )-deficient mice. 4,5 Already this moderate decrease in renal function increases atherosclerotic lesion size paralleling the increase in atherosclerotic lesion burden observed in humans. 4,6,7 These atherosclerotic mouse strains have been employed for the investigation of mechanisms of increase in atherosclerosis in moderate renal impairment.…”

“…4,6,7 These atherosclerotic mouse strains have been employed for the investigation of mechanisms of increase in atherosclerosis in moderate renal impairment. 5,7,8 Inflammatory leukocytes promote growth and regulate composition and thereby stability of the atherosclerotic plaque. [9][10][11] T cells are major modifiers of plaque formation among adaptive immune cells.…”

“…12 We have shown that the T H17 cell cytokine IL-17A aggravates atherosclerosis in renal impairment and is required for enhanced aortic CD11b + CD11c + myeloid cell accumulation in this condition. 5 Myeloid cells that phagocytose lipids and form foam cells accumulate in the atherosclerotic lesion due to both monocyte immigration and local proliferation. 13 During atherogenesis, CD11c expression on aortic CD11b + myeloid cells increases.…”

“…18 In moderate renal impairment, aortic CD11b + CD11c + myeloid cell numbers expand significantly. 5 Aortic myeloid cells mostly derive from peripheral blood monocytes at early stages of atherosclerosis development. 13 Multiple chemokines have been implicated in this, including fractalkine receptor CX3CR1, which promotes lesion progression.…”