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Review
, 30 (2), 199-209

Macrophage-mediated Injury and Repair After Ischemic Kidney Injury

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Review

Macrophage-mediated Injury and Repair After Ischemic Kidney Injury

Sarah C Huen et al. Pediatr Nephrol.

Abstract

Acute ischemic kidney injury is a common complication in hospitalized patients. No treatment is yet available for augmenting kidney repair or preventing progressive kidney fibrosis. Animal models of acute kidney injury demonstrate that activation of the innate immune system plays a major role in the systemic response to ischemia/reperfusion injury. Macrophage depletion studies suggest that macrophages, key participants in the innate immune response, augment the initial injury after reperfusion but also promote tubular repair and contribute to long-term kidney fibrosis after ischemic injury. The distinct functional outcomes seen following macrophage depletion at different time points after ischemia/reperfusion injury suggest heterogeneity in macrophage activation states. Identifying the pathways that regulate the transitions of macrophage activation is thus critical for understanding the mechanisms that govern both macrophage-mediated injury and repair in the postischemic kidney. This review examines our understanding of the complex and intricately controlled pathways that determine monocyte recruitment, macrophage activation, and macrophage effector functions after renal ischemia/reperfusion injury. Careful delineation of repair and resolution pathways could provide therapeutic targets for the development of effective treatments to offer patients with acute kidney injury.

Figures

Figure 1
Figure 1. Macrophage Activation and Effector Responses after Renal I/R
Early after renal I/R injury, PMNs and NK T cells are recruited to the kidney. ROS and IFNγ released by activated PMNs and NK T cells as well as tubule cell-derived DAMPs promote M1 activation of infiltrating monocytes. M1 macrophages in turn upregulate iNOS leading to the production of nitric oxide that can promote local formation of peroxynitrites and induction of tubular cell apoptosis. S1P3 signaling on resident DCs promotes Th1 activation of NK T cells. SIGIRR and A2AR on DCs provide negative feedback to limit the level of pro-inflammatory activation. During the proliferative tubular repair phase, macrophage derived BRP-39 and Wnt7b promote tubular regeneration by limiting tubular apoptosis. Serum amyloid P (pentraxin-2) induces immunoregulatory macrophages that express IL-10 and promote resolution of the inflammatory process thereby limiting the development of fibrosis. The mechanism by which macrophages promote renal fibrosis after I/R injury is unclear. A2AR, adenosine A2 receptor receptor; DAMP, danger associated molecular pattern; DC, dendritic cells; I/R, ischemia/reperfusion; IFNγ, interferon-γ; MΦ, macrophage; M1, M1 macrophage; M2a, M2 wound healing macrophage; ROS, reactive oxygen species; PMN, polymorphonuclear neutrophils; NK, natural killer T cells; NO, nitric oxide, S1P3, Sphingosine 1-phosphate receptor-3; SIGIRR, Single Ig IL-1-related receptor.

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