title: CXCR6 deficiency ameliorated myocardial ischemia/reperfusion injury by inhibiting infiltration of monocytes and IFN-γ-dependent autophagy.
abstract: 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.
  
  
  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-γ and IFN-γ-dependent autophagy were found to be significantly attenuated in CXCR6 KO mice. Further data showed that cardiac-enhanced IFN-γ secretion was not induced by cardiomyocytes, but by infiltrated monocytes in the myocardium in response to I/R injury. In vivo injection of IFN-γ and in vitro co-cultured cardiomyocytes with CD11b+ monocytes confirmed IFN-γ 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-γ.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, 180 Feng Lin Road, Shanghai 200032, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Yang
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Qiu
authors.forename: Chaoneng
authors.initials: C
authors.lastname: Wu
authors.forename: Wenbin
authors.initials: W
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Youen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002464:Cell Migration Inhibition / Q000502:physiology; D018920:Coculture Techniques; D007371:Interferon-gamma / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D054387:Receptors, CXCR / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000075744:Receptors, CXCR6
chemical_list: C482906:Cxcr6 protein, mouse; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D007371:Interferon-gamma