The immunomodulating role of patrolling monocytes in acute kidney injury

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Acute kidney injury (AKI) is a frequent condition in hospitalized patients and increases mortality. Leukocytes infiltrate the kidney and promote a local inflammatory milieu which leads to renal impairment and chronic fibrosis. Monocytes play an outstanding role in AKI as they orchestrate the immune response, repair mechanisms and macrophage functions. The subset of non-classical monocytes (NCM, patrolling monocytes, Ly6Clow) patrol the vascular endothelium in search of inflammatory cues. They exert a broad immunomodulatory effector function including interactions with the adaptive and innate immune response. Preliminary data show that a lack of NCM results in excessive neutrophil invasion in early AKI. However, a detailed understanding during kidney inflammation is missing. This project will address the role of intravascular NCM in a mouse model of ischemia reperfusion injury. Using NCM-deficient mice, adoptive transfer, a vascular flushing technique and adhesion receptor blocking antibodies, the impact of NCM on kidney injury, vascular immune response networks, downstream leukocyte infiltration and the mononuclear phagocyte axis will be investigated at the acute inflammation and resolution stage of AKI. Intravital microscopy is employed to characterize patrolling behavior and inter-leukocyte interactions in the renal circulation. The heterogeneous leukocyte landscape will be analyzed by multiplexed imaging to resolve alterations of mononuclear phagocytes in function of NCM-deficiency. Together, these data will dissect the complex role of NCM as vascular gatekeepers in kidney inflammation and might uncover new targets for the diagnosis and treatment of AKI.