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

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.

Role of the CCL20/CCR6 axis in tubular epithelial cell injury: Kidney‐specific translational insights from acute kidney injury to chronic kidney disease

“…Male C57BL/6 (B6) mice (aged 8 weeks) were procured from the Orient Company (Seoul, Republic of Korea) and housed in a pathogen‐free animal facility. Renal ischemia–reperfusion injury (IRI) was induced unilaterally and bilaterally following previously established experimental protocols 19–24 . Prior to the procedure, wild‐type mice were anesthetized via an intraperitoneal injection using an anesthetic solution of tiletamine mixed with zolazepam (1:1) (Zoletil; 30 mg/kg of body weight; Virbac, USA) and xylazine (25 mg/mL) (Rompun; 10 mg/kg of body weight; Bayer, Canada) 25 .…”

“…25 Subsequently, bilateral flank incisions were performed, and both renal pedicles were carefully dissected and clamped using a microvascular clamp (Roboz Surgical Instrument, Gaithersburg, MD, USA) for 30 min. 19,20,23,26 Throughout the procedure, 2 mL of sterile saline at 40°C (1 mL during ischemia and 1 mL during reperfusion) was administered into the peritoneal cavity. Body temperatures were consistently monitored and maintained at 37°C during the renal IRI process.…”

“…37,38 Macrophages are a major source of chemokine expression in AKI. Chemokine expression also affects macrophage migration 23 and subsequently upregulates reactive oxygen radicals and adhesion molecules. 39 Among the chemokines involved in TEC injury, CCL20 and its role were first elucidated by Ramos et al using a model of folic acid-induced AKI, 40 and CCL20 blockade aggravated renal injury caused by high-dose folic acid.…”

Major signaling pathways and key mediators of macrophages in acute kidney injury (Review)

“…Chemokine receptor 5 (CCR5) is a pivotal regulator of the inflammatory cascade response of macrophages in the kidney, and its deficiency contributes to the activation of M2 macrophages ( Fig. 2 ; Table I ) ( 109 ). Therefore, blocking CCR5 may be helpful in the treatment of I/R-AKI.…”

CXC Chemokine Receptor 2 Accelerates Tubular Cell Senescence and Renal Fibrosis via β-Catenin-Induced Mitochondrial Dysfunction

“…They play an essential role in leukocyte migration ( Kufareva et al, 2015 ). Recent studies showed that CXCR family is highly involved in kidney diseases ( Ye et al, 2018 ; Yahong Liu et al, 2020 ; Yoo et al, 2020 ). In our previous study, we have found that CXCR4 promotes tubular injury and renal fibrosis through activating β-catenin ( Mo et al, 2017 ; Yahong Liu et al, 2020 ).…”