Chemokine receptor 5 blockade modulates macrophage trafficking in renal ischaemic-reperfusion injury

J Cell Mol Med. 2020 May;24(10):5515-5527. doi: 10.1111/jcmm.15207. Epub 2020 Mar 30.

Abstract

Chemokine receptor 5 (CCR5) is a pivotal regulator of macrophage trafficking in the kidneys in response to an inflammatory cascade. We investigated the role of CCR5 in experimental ischaemic-reperfusion injury (IRI) pathogenesis. To establish IRI, we clamped the bilateral renal artery pedicle for 30 min and then reperfused the kidney. We performed adoptive transfer of lipopolysaccharide (LPS)-treated RAW 264.7 macrophages following macrophage depletion in mice. B6.CCR5-/- mice showed less severe IRI based on tubular epithelial cell apoptosis than did wild-type mice. CXCR3 expression in CD11b+ cells and inducible nitric oxide synthase levels were more attenuated in B6.CCR5-/- mice. B6.CCR5-/- mice showed increased arginase-1 and CD206 expression. Macrophage-depleted wild-type mice showed more injury than B6.CCR5-/- mice after M1 macrophage transfer. Adoptive transfer of LPS-treated RAW 264.7 macrophages reversed the protection against IRI in wild-type, but not B6.CCR5-/- mice. Upon knocking out CCR5 in macrophages, migration of bone marrow-derived macrophages from wild-type mice towards primary tubular epithelial cells with recombinant CCR5 increased. Phospho-CCR5 expression in renal tissues of patients with acute tubular necrosis was increased, showing a positive correlation with tubular inflammation. In conclusion, CCR5 deficiency favours M2 macrophage activation, and blocking CCR5 might aid in treating acute kidney injury.

Keywords: CC chemokine receptor 5; acute kidney injury; bilateral ischaemia-reperfusion injury; chemokine; macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / etiology*
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Adoptive Transfer
  • Animals
  • Biomarkers
  • Biopsy
  • CCR5 Receptor Antagonists / pharmacology*
  • Cytokines / metabolism
  • Immunohistochemistry
  • Immunophenotyping
  • Macrophage Activation / immunology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • RAW 264.7 Cells
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism*
  • Reperfusion Injury / etiology*
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Biomarkers
  • CCR5 Receptor Antagonists
  • Cytokines
  • Receptors, CCR5