IL-22对阿霉素肾病肾损伤的影响及诱导性巨噬细胞对其介导损伤的干预作用

Accumulation of Macrophage is closely related with renal structural damage and renal dysfunction. Here, Our group first reported that M2 macrophages modified by IL-10/TGF-βsignificantly attenuated renal inflammation, structuralinjury, and functional decline in murine Adriamycin nephrosis (AN). M2 macrophage induced regulatory T cells from CD4+CD25-T cells in vitro, and increased the number of regulatory T cells in renal draining lymph nodes in AN. These cells inhibited CD4+ T cell proliferation. There are several T lymphocyte subsets, including Th1, Th2, Treg, Th17 and Th22. Whether M2 macrophages reduce renal injury through the suppression of Th22 in vivo? Recently, we found that IL-22 expression was significantly higher in AN mice than that in normal mice, and IL-22 expression obviously reduced in AN mice after treated withM2 macrophages. Also, we found similar results in the focal segmental glomerulonephritis patients before and after hormone therapy. Combined experimental basis of before, We put hypothesis that Th22 cells secreting IL-22 may be the key pathogenic factor in chronic glomerulonephritis, whereas M2 macrophages may reduce inflammation by suppressing Th22 cells in diseased kidney. The topic will be performed through clinical cases, animal model to investigate the role of IL-22 secreting cells in the pathogenesis of chronic glomerulonephritis. The purpose of this study is to reveal the M2 macrophages protect against renal injury through inhibition of IL-22 secreting cells, and provide a theoretical basis for the macrophage therapy.

巨噬细胞聚集与肾结构损伤和肾功能紊乱的密切相关。本课题组首次报道了发现诱导性M2型巨噬细胞的过继性细胞免疫疗法可通过抑制提高肾脏局部淋巴结Treg数量，同时抑制肾脏侵润T细胞数量减轻阿霉素肾病的肾脏损伤。T细胞亚群众多，M2巨噬细胞究竟通过抑制哪种T细胞亚群发挥作用呢？近来我们发现阿霉素肾病鼠IL-22水平明显增高，接受M2型巨噬细胞疗法后，IL-22水平明显降低，同样的我们在人局灶性节段性肾小球肾炎患者激素治疗前后也发现类似的情况，联合之前的实验基础，我们提出分泌IL-22的Th22细胞可能是慢性肾小球肾炎疾病肾损伤的关键因素，而M2型巨噬细胞疗法可能是通过抑制Th22细胞的肾脏侵润减轻炎症的设想，本课题将通过临床病例分析、动物模型等详细探讨IL-22及其分泌细胞在慢性肾小球肾炎发病中作用，揭示M2型巨噬细胞可能通过Treg抑制分泌IL-22细胞的浸润，为巨噬细胞疗法提供理论依据。

巨噬细胞聚集与肾结构损伤和肾功能紊乱的密切相关。本课题组首次报道了发现诱导性M2型巨噬细胞的过继性细胞免疫疗法可通过抑制提高肾脏局部淋巴结Treg数量，同时抑制肾脏侵润T细胞数量减轻阿霉素肾病的肾脏损伤。近来我们发现阿霉素肾病鼠IL-22水平明显增高，接受M2型巨噬细胞疗法后，IL-22水平明显降低，同样的我们在人局灶性节段性肾小球肾炎患者激素治疗前后也发现类似的情况，联合之前的实验基础，我们提出分泌IL-22的Th22细胞可能是慢性肾小球肾炎疾病肾损伤的关键因素，而M2型巨噬细胞疗法可能是通过抑制Th22细胞的肾脏侵润减轻炎症的设想，本课题将通过临床病例分析、动物模型等详细探讨IL-22及其分泌细胞在慢性肾小球肾炎发病中作用。结果显示①慢性肾小球肾炎患者血清IL-22水平明显高于正常人，治疗后显著下降，与肾脏功能呈现负相关。②肾脏活体转染pIL-22-luc后发现AN小鼠7h、24h、48h后，AN组小鼠的荧光强度均明显高于同时间段的健康对照组;③AN鼠模型回输M2巨噬细胞后可减轻肾脏结构破坏；④AN鼠尾静脉注射IL-22中和抗体2W，可减轻肾脏结构破坏；⑤IL-22R阻断性抗体可减少原代足细胞F-actin的聚集；⑥在AN鼠模型中IL-22的主要来源细胞为CD3-NKp46+CD4+RORγt+的固有免疫样细胞LTi，而非之前预测的CD3+CD4+IL-22+IL-17A-Th22；⑦清除AN鼠模型中LTi细胞，可减低血清中IL-22水平，同时减轻肾脏纤维化和肾小球硬化。⑧IL-22可影响原代肾脏上皮细胞的形态和膜表面粘附分子ICAM-1表达。⑨IL-17是与IL-22分泌高度相关的细胞因子，其家族成员IL-17E也叫IL-25，课题组发现在肾缺血再灌注模型IRI中，IL-25可以通过增加肾脏2型先天淋巴细胞(ILC2),以及多能祖2型细胞(MPPtype2)诱导强烈的Th2免疫应答。此外,IL-25可以增加血清和肾脏中IL-4、10、13的水平，过继转移ILC2或MPPtype2细胞不仅减少肾脏功能和组织学损伤，也可以也诱导肾脏M2巨噬细胞增多。该研究结果有助于阐明IL-22在肾小球肾炎中的作用机制，为进一步研究肾脏疾病提供了理论依据。