The immunomodulating role of patrolling monocytes in acute kidney injury

急性肾损伤(AKI)是住院患者中的一种常见情况，并增加了死亡率。白细胞渗入肾脏，促进局部炎症环境，导致肾脏损伤和慢性纤维化。单核细胞在AKI中扮演着重要的角色，因为它们协调免疫反应、修复机制和巨噬细胞的功能。非经典单核细胞亚群(NCM、巡逻单核细胞、Ly6Clow)在血管内皮细胞内巡逻，寻找炎症信号。它们发挥着广泛的免疫调节效应功能，包括与适应性免疫反应和先天免疫反应的相互作用。初步数据显示，在AKI早期，缺乏NCM会导致中性粒细胞过度侵袭。然而，对肾脏炎症过程的详细了解尚不清楚。该项目将解决血管内NCM在小鼠缺血再灌注损伤模型中的作用。利用NCM缺陷小鼠、过继移植、血管冲洗技术和黏附受体阻断抗体，将在AKI急性炎症和缓解阶段观察NCM对肾脏损伤、血管免疫反应网络、下游白细胞浸润和单核巨噬细胞轴的影响。活体显微镜被用来描述肾循环中的巡逻行为和白细胞间的相互作用。在NCM缺乏症患者中，单核巨噬细胞的功能改变将通过多路成像来分析异质性白细胞的情况。总之，这些数据将剖析NCM在肾脏炎症中作为血管守门人的复杂作用，并可能为AKI的诊断和治疗发现新的靶点。

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.