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.
Highlights
Renal ischaemic-reperfusion injury (IRI) is a complicated orchestrated event that elicits diverse immunological responses
The role of T lymphocytes in this process is well known[20-23]: when renal tubular cells are injured or stimulated in various ways, including activation by the complement system, expression of Toll-like receptors increases, promoting the production of chemokines such as monocyte chemo-attractant protein 1 (MCP-1), CXCL8 and RANTES.[24,25]
We confirmed the results of previous studies regarding T cells and their relationship with IRI in a B6.Chemokine receptor 5 (CCR5)−/− mouse model.[26]
Summary
Renal ischaemic-reperfusion injury (IRI) is a complicated orchestrated event that elicits diverse immunological responses. Monocytes/ macrophages, which exhibit great pliability, are important components of renal IRI. Their presence in the kidneys is closely correlated with a loss of renal function,[1-3] and plasticity of macrophages affects the incidence of acute renal damage owing to chronic fibrosis.[4-6]. CCR5 is mainly associated with organ development, including angiogenesis, haematopoiesis, metastasis and chemotaxis. It is encoded on chromosome 3p21 and expressed by various immune cells such as resting T lymphocytes that have memory and effector T-cell phenotypes, monocytes, macrophages and immature dendritic cells.[7]. Several ligands, including RANTES (regulated on activation, normal T cell expressed and secreted/CCL5), monocyte chemo-attractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1α and MIP-1β, react with CCR5, are activated by CCR5 retroactive to CCR5 ligands
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