CXCR4 blockade in macrophage promotes angiogenesis in ischemic hindlimb by modulating autophagy

J Mol Cell Cardiol. 2022 Aug:169:57-70. doi: 10.1016/j.yjmcc.2022.05.002. Epub 2022 May 18.

Abstract

Chemokine receptor CXCR4 plays a crucial role in leukocyte recruitment and inflammation regulation to influence tissue repair in ischemic diseases. Here we assessed the effect of CXCR4 expression in macrophages on angiogenesis in the ischemic hindlimb of a mouse. Inflammatory cells were increased in the ischemic muscles of hindlimb, and CXCR4 was highly expressed in the infiltrated macrophages but not in neutrophils. Myeloid-specific CXCR4 knockout attenuated macrophage infiltration and subsequent reduced inflammatory response in the ischemic hindlimb, accompanied with better blood reperfusion and higher capillary density as compared with that in LysM Cre+/- (Cre) mice. Similar outcomes were also observed in CRE mice whose bone marrow cells were replaced with those from CXCR4-deficient mice. Gene ontology cluster analysis reviewed that Decorin, a negative regulator of angiogenesis, was reduced in CXCR4-deficient macrophages. CXCR4-deficient macrophages were less inducible into M1 phase by lipopolysaccharide and more favorable for M2 polarization under oxygen/glucose deprivation condition. Enhanced autophagy was detected in CXCR4-deficient macrophages, which was associated with less expression of both Decorin and the inflammatory cytokines. In summary, myeloid-specific CXCR4 deficiency reduced monocyte infiltration and the secretion of inflammatory cytokines and Decorin from macrophages, thus blunting inflammation response and promoting angiogenesis in the ischemic hindlimb.

Keywords: Autophagy; CXCR4; Decorin; Hindlimb ischemia; Macrophage polarization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Cytokines / metabolism
  • Decorin / metabolism
  • Hindlimb / blood supply
  • Inflammation / metabolism
  • Ischemia* / metabolism
  • Macrophages* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / metabolism
  • Receptors, CXCR4 / metabolism*

Substances

  • CXCR4 protein, mouse
  • Cytokines
  • Decorin
  • Receptors, CXCR4