Phenotype and influx kinetics of leukocytes and inflammatory cytokine production in kidney ischemia/reperfusion injury

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Ischemia/reperfusion (IR) injury is a leading cause of acute kidney injury (AKI). Various forms of cardiac and vascular surgery, kidney transplantation, sepsis, radiocontrast agents and other nephrotoxins have been implicated in ischemic kidney damage.1 These acute insults trigger inflammation and cause tubular epithelial cell (TEC) death, impairing renal function.9 Fortunately, kidneys have a capacity to repair endogenously, although this appears limited. These repair processes revolve around reducing the initial inflammatory response, tubular epithelial cell replacement and remodelling of the extracellular matrix.
Macrophages constitute a heterogeneous population implicated in both IR‐induced inflammation and tissue repair due to varied activation states that they acquire in response to microenvironmental cues. While the M1/M2 paradigm describing macrophage polarization as pro‐inflammatory (M1) or anti‐inflammatory/immunomodulatory/reparative (M2) is useful, it underestimates the complexity of macrophage activation in the setting of kidney IR injury.
Conceivably, distinct subpopulations of monocytes with varied characteristics may differentiate into macrophages of a specific activation state. In a study using a murine unilateral ureteral obstruction (UUO) model of kidney disease, distinct bone marrow (BM)‐derived monocytes, defined by the level of Ly6C expression, were reported to differentiate into phenotypically different mature macrophages.10 In particular, Ly6Clow monocytes were found to transition into profibrotic, M2 macrophages.10 The temporal down‐regulation of Ly6C also provides a marker of murine monocyte maturation.11 Among the first to characterize these monocytes, Sunderkotter et al. demonstrated that following diphtheria toxin (DT)‐mediated depletion of CD11b+ cells in CD11bDTR mice, BM‐derived Ly6Chigh cells were the first monocytes to repopulate the blood and their maturation resulted in the progressive emergence of Ly6Clow and finally Ly6C− monocytes and macrophages. In addition, the immature Ly6Chigh monocytes preferentially homed to sites of both acute and chronic inflammation.11
Insight into the nature of macrophage activation and the mechanisms by which they modulate the immune response to IR injury can be gained through examining their interplay with neutrophils. Neutrophils are early responders to IR injury where they promote inflammation and contribute to tissue damage through the production of reactive oxygen species (ROS), proteases and cytokines, including interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α, interleukin (IL)‐6, IL‐4 and IL‐10.12 Macrophages are known to recruit neutrophils to sights of inflammation, which in turn recruit inflammatory monocytes.15 However, mechanisms exist to regulate neutrophil recruitment and survival in order to actively reduce inflammation.15 For example, heightened production of TNF by macrophages also promotes neutrophil apoptosis16 and macrophage phagocytosis of apoptotic neutrophils stimulates the production of anti‐inflammatory mediators, including transforming growth factor (TGF)‐β.17
This study is the first to perform a comprehensive characterization of the IR injury model of AKI, specifically focusing on epithelial cells and subpopulations of myeloid cells throughout the inflammatory and remodelling phases of the disease. Flow cytometry was predominantly used to characterize the loss, infiltration and maturation of specific cell types in conjunction with cytokine production. This characterization will provide a reference point for future studies designed to manipulate cell function in order to promote endogenous kidney repair.
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