T Cell CX3CR1 Mediates Excess Atherosclerotic Inflammation in Renal Impairment.

Abstract

Reduced kidney function increases the risk for atherosclerosis and cardiovascular death. Leukocytes in the arterial wall contribute to atherosclerotic plaque formation. We investigated the role of fractalkine receptor CX3CR1 in atherosclerotic inflammation in renal impairment. Apoe(-/-) (apolipoprotein E) CX3CR1(-/-) mice with renal impairment were protected from increased aortic atherosclerotic lesion size and macrophage accumulation. Deficiency of CX3CR1 in bone marrow, only, attenuated atherosclerosis in renal impairment in an independent atherosclerosis model of LDL receptor-deficient (LDLr(-/-)) mice as well. Analysis of inflammatory leukocytes in atherosclerotic mixed bone-marrow chimeric mice (50% wild-type/50% CX3CR1(-/-) bone marrow into LDLr(-/-) mice) showed that CX3CR1 cell intrinsically promoted aortic T cell accumulation much more than CD11b(+)CD11c(+) myeloid cell accumulation and increased IL-17-producing T cell counts. In vitro, fewer TH17 cells were obtained from CX3CR1(-/-) splenocytes than from wild-type splenocytes after polarization with IL-6, IL-23, and TGFβ Polarization of TH17 or TREG cells, or stimulation of splenocytes with TGFβ alone, increased T cell CX3CR1 reporter gene expression. Furthermore, TGFβ induced CX3CR1 mRNA expression in wild-type cells in a dose- and time-dependent manner. In atherosclerotic LDLr(-/-) mice, CX3CR1(+/-) T cells upregulated CX3CR1 and IL-17A production in renal impairment, whereas CX3CR1(-/-) T cells did not. Transfer of CX3CR1(+/-) but not Il17a(-/-) T cells into LDLr(-/-)CX3CR1(-/-) mice increased aortic lesion size and aortic CD11b(+)CD11c(+) myeloid cell accumulation in renal impairment. In summary, T cell CX3CR1 expression can be induced by TGFβ and is instrumental in enhanced atherosclerosis in renal impairment.

• Authors: Lei Dong, Johannes Nordlohne, Shuwang Ge, Barbara Hertel, Anette Melk, Song Rong, Hermann Haller, Sibylle von Vietinghoff
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 27 Issue 6 Pg. 1753-64 (06 2016) ISSN: 1533-3450 [Electronic] United States
• PMID: 26449606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by the American Society of Nephrology.

Chemical References

• CX3C Chemokine Receptor 1
• Cx3cr1 protein, mouse
• Receptors, Chemokine

Topics

• Animals
• Atherosclerosis (etiology)
• CX3C Chemokine Receptor 1
• Cells, Cultured
• Female
• Inflammation (etiology)
• Male
• Mice
• Receptors, Chemokine (genetics, physiology)
• Renal Insufficiency (complications)