Smooth muscle cells-derived CXCL10 prevents endothelial healing through PI3Kγ-dependent T cells response

Abstract

Aims: Defects in efficient endothelial healing have been associated with complication of atherosclerosis such as post-Angioplasty neoatherosclerosis and plaque erosion leading to thrombus formation. However, current preventive strategies do not consider re-endothelialization in their design. Here, we investigate mechanisms linking immune processes and defect in re-endothelialization. We especially evaluate if targeting phosphoinositide 3-kinase γimmune processes could restore endothelial healing and identify immune mediators responsible for these defects. Methods and results: Using in vivo model of endovascular injury, we showed that both ubiquitous genetic inactivation of PI3Kγand hematopoietic cell-specific PI3Kγdeletion improved re-endothelialization and that CD4+ T-cell population drives this effect. Accordingly, absence of PI3Kγactivity correlates with a decrease in local IFNγsecretion and its downstream interferon-inducible chemokine CXCL10. CXCL10 neutralization promoted re-endothelialization in vivo as the same level than those observed in absence of PI3Kγsuggesting a role of CXCL10 in re-endothelialization defect. Using a new established ex vivo model of carotid re-endothelialization, we showed that blocking CXCL10 restore the IFNγ-induced inhibition of endothelial healing and identify smooth muscle cells as the source of CXCL10 secretion in response to Th1 cytokine. Conclusion: Altogether, these findings expose an unforeseen cellular cross-Talk within the arterial wall whereby a PI3Kγ-dependent T-cell response leads to CXCL10 production by smooth muscle cells which in turn inhibits endothelial healing. Therefore, both PI3Kγand the IFNγ/CXCL10 axis provide novel strategies to promote endothelial healing.