CXCR6 deficiency ameliorated myocardial ischemia/reperfusion injury by inhibiting infiltration of monocytes and IFN-γ-dependent autophagy

Background: Emerging evidence shows that the chemokine CXCL16 plays an important role in the pathogenesis of myocardial remodeling and development of heart failure following ischemia/reperfusion (I/R) injury. CXCR6, the receptor for CXCL16, is also critically involved. However, the underlying mechanism remained uncertain, and the aim of this research was to investigate this mechanism in CXCR6 knockout (KO) mice. Methods and results: CXCR6 KO mice and wild type (WT) mice had no overt phenotype at baseline in the absence of injury, but difference was shown in response to I/R induction. Compared with WT mice, CXCR6 KO mice exhibited a lower infarction size (31.86 +/- 1.808% vs. 43.09 +/- 1.519%), and better cardiac function (measured by LVEF, LVFS, + dp/dt, LVEDP, and LVSP) following I/R. Moreover, cardiac levels of IFN-gamma and IFN-gamma-dependent autophagy were found to be significantly attenuated in CXCR6 KO mice. Further data showed that cardiac-enhanced IFN-gamma secretion was not induced by cardiomyocytes, but by infiltrated monocytes in the myocardium in response to I/R injury. In vivo injection of IFN-gamma and in vitro co-cultured cardiomyocytes with CD11b + monocytes confirmed IFN-gamma activated autophagic response, and induced cardiac dysfunction in a paracrine manner. Conclusions: The study suggested that since disruption of the CXCL16/CXCR6 signaling cascade had a cardio-protective effect against I/R injury, the underlying mechanism might be that I/R triggered the infiltration of monocytes into the myocardium, and induced cardiac autophagy through CXCL16/CXCR6-dependent paracrine secretion of IFN-gamma. Crown Copyright (c) 2012 Published by Elsevier Ireland Ltd. All rights reserved.