Chemokine CXCL10 Promotes Atherogenesis by Modulating the Local Balance of Effector and Regulatory T Cells

Abstract

Background-Studies to define the overall contribution of lymphocytes to lesion formation in atherosclerosis-susceptible mice have demonstrated relatively subtle effects; the use of lymphocyte-deficient mice, however, compromises both the effector and regulatory arms of the immune system. Here, we tested the hypothesis that deletion of CXCL10 (IP-10), a chemokine specific for effector T cells that has been localized within atherosclerotic lesions, would significantly inhibit atherogenesis. Methods and Results-Compound deficient ApoeϪ/Ϫ /Cxcl10 Ϫ/Ϫ mice fed a Western-style diet for either 6 or 12 weeks demonstrated significant reductions in atherogenesis as compared with Apoe Ϫ/Ϫ controls, as assessed by both aortic en face and cross-sectional analyses. Immunohistochemical studies revealed a decrease in the accumulation of CD4 ϩ T cells, whereas quantitative polymerase chain reaction analysis of lesion-rich aortic arches demonstrated a marked reduction in mRNA for CXCR3, the CXCL10 chemokine receptor. Although overall T-cell accumulation was diminished significantly, we found evidence to suggest that regulatory T-cell (T reg ) numbers and activity were enhanced, as assessed by increased message for the T reg -specific marker Foxp3, as well as increases in immunostaining for the T reg -associated cytokines interleukin-10 and transforming growth factor-␤1. We also documented naturally occurring T reg cells in human atherosclerotic lesions. Conclusions-We provide novel evidence for a functional role for the effector T-cell chemoattractant CXCL10 in atherosclerotic lesion formation by modulating the local balance of the effector and regulatory arms of the immune system.

Distinctive Expression of Chemokines and Transforming Growth Factor-β Signaling in Human Arterial Endothelium during Atherosclerosis

“…30 -34 In mouse models, elevated expression levels of these genes have also been identified in atherosclerotic plaques, functional blocking of the majority of these genes has been shown to reduce lesion size and leukocyte recruitment. 31,[35][36][37][38] However, the plaque stage-specific expression patterns of most of these genes differ between our human data and the data from the mice. Important factors that possibly explain these interspecies discrepancies are the species differences in time span of plaque development and the differences in the methodology, analysis, interpretation of the microarray data, as has recently been discussed in detail.…”

Lymphocytes in obesity-related adipose tissue inflammation

“…The protein known as regulated upon activation, normal T cell expressed and secreted (RANTES), which is secreted by murine and human adipocytes and by cells of the SVF [3], or CCL20, which is produced by human adipocytes [33], and CXCL12, which is mainly secreted by human and murine SVF cells [38], may promote the accumulation of lymphocytes into WAT through binding to their receptors CCR5, CCR6 and CXCR4, respectively. Furthermore, the pathway regulated by the chemokine CXCL10/chemokine IFN-γ inducible protein-10 (IP10), which is expressed by human and murine adipocytes [39], and its receptor CXCR3, which is present on T cells, may alter the balance between effector T cells and regulatory T cells (Tregs) [40] and contribute to the recruitment of T cells into adipose tissue [41]. In turn, lymphocytes may modulate adipokine secretion by adipocytes via activation of the CD40-CD40L pathway [42].…”

Systemic chemokine levels, coronary heart disease, and ischemic stroke events

“…34,35 It is worth noting that RANTES/CCR5 signaling and IP-10 are known promoters of T-cell recruitment and activation. 37,38 In addition, RANTES/ CCR5 restrains IL-10 production 37 while IP-10 inhibits regulatory T-cell recruitment, 38 2 pathways recently shown to play critical roles in the control of the inflammatory response to brain injury and in brain protection after an ischemic insult. 34,35 All these putative mechanisms arise from experimental models in which chemokine levels were elevated at the time or after brain injury.…”