Interleukin-22 in kidney regeneration

再生肾组织的能力决定了急性肾损伤(AK)和慢性肾脏疾病(CKD)的结局。最近的数据证明，肾内单核巨噬细胞(不同的树突状细胞和巨噬细胞表型)不仅可以促进肾脏损伤，还可以促进肾脏再生，但相关的促再生介质仍不清楚。利用一个新开发的筛选系统，我们确定了最近发现的IL-22就是这样一个潜在的介体。我们项目特有的初步数据显示，垂死的肾小管上皮细胞释放TLR4激动剂成分，刺激肾树突状细胞分泌IL-22。IL-22通过IL-22R介导的MAPK和ERK信号通路加速损伤肾小管上皮细胞的再生。目前，还没有关于IL-22和肾脏的公开数据。在这个项目中，我们计划研究这一以前未知的肾脏再生机制。1.研究IL-22和IL-22R在以下动物模型中的表达：完全恢复(AKI)或进行性肾小管萎缩和纤维化(CKD)后的AKI，马兜铃酸诱导的AKI/CKD和单侧输尿管梗阻后肾纤维化。2.研究TLR激动剂、AhR激动剂和Notch激动剂对IL-22诱导的调节作用。3.体外研究IL-22介导的肾小管上皮细胞、肾小管祖细胞、肾内皮细胞和肾成纤维细胞的再生。此外，我们将在体内使用IL-22缺陷小鼠、IL-22中和抗体、去除产生IL-22的免疫细胞亚群以及重组IL-22来研究这一方面。4.最后，我们将评估重组IL-22对上述小鼠肾损伤模型的治疗潜力。我们期望这个项目的数据将揭示一个以前未知的肾脏再生机制。最重要的是，这一机制具有治疗应用的潜力，例如，通过重组IL-22或其他IL-22R激动剂来加速AKI的恢复和减缓CKD的进展。

The capacity to regenerate renal tissue determines outcomes of acute kidney injury (AK) and chronic kidney disease (CKD). Recent data document that intrarenal mononuclear phagocytes (diverse dendritic cell and macrophage phenotypes) not only drive kidney injury but also kidney regeneration but the associated pro-regeneratory mediators remain unknown. Using a newly developed screening system we identified the recently discovered interleukin IL-22 as such a potential mediator. Our project-specific preliminary data demonstrate that dying tubular epithelial cells release TLR4 agonistic components that stimulate renal dendritic cells to secrete IL-22. IL-22 accelerates the regeneration of of injured tubular cells via IL-22R-mediated MAPK and Erk signaling. Currently, there are no published data on IL-22 and the kidney. In this project we plan to study this previously unknown mechanism of kidney regeneration. We plan to: 1. Study the expression of IL-22 and IL-22R in the following animal models: post-ischemic AKI followed bei either full recovery (AKI) or by progressive tubular atrophy and fibrosis (CKD), aristolochic acid-induced AKI/CKD, and renal fibrosis upon unilateral ureteral obstruction. 2. To study the regulation of IL-22 induction including the effect of TLR agonists, Ahr agonists, and Notch agonists. 3. Characterizing the IL-22-mediated regeneration of tubular epithelial cells, tubular progenitor cells, renal endothelial cells, and renal fibroblasts in vitro. In addition we will study this aspect in vivo using IL-22-deficient mice, IL-22 neutralizing antibodies, depletion of IL-22-producing immune cell subsets, and reconstitution with recombinant IL-22. 4. Finally, we will evaluate the therapeutic potential of recombinant IL-22 on the aforementioned mouse models of kidney injury. We expect that data from this project will overt a previously unknown mechanism of kidney regeneration. Most importantly, this mechanism holds the potential for therapeutic applications, e.g. to accelerate AKI recovery and to slow down the progression of CKD with recombinant IL-22 or other IL-22R agonists.