ILC1/ILC2细胞免疫特性在脂肪组织纤维化发生发展中的作用及其机制研究

Innate and adaptive immune cell responses in adipose tissue have critical roles in the regulation of metabolic homeostasis. Imbalance of the immune homeostasis drives the emerging of fibrosis and inflammation in adipose tissue, however, the provoking mechanism involved remains unclear. Recently, it is reported that abnormal accumulation of group 1 innate lymphoid cells (ILC1) in adipose tissue drives polarization and infiltration of proinflammatory M1 macrophages, and promotes insulin resistance, while group 2 innate lymphoid cells (ILC2) maintains tissue resident of M2 macrophages and metabolic homeostasis. In our preliminary study, we found that adipose tissue of obese individuals showed obvious fibrosis compared to lean individuals. Meanwhile, both the ratio of ILC1 to ILC2 and the ratio of M1 to M2 macrophage were higher in obese individuals. Further, the abnormal fibrosis and activation of immune cells in adipose tissue were aggravated in subjects of obese type 2 diabetes. These findings suggest that abnormal increased ratio of ILC1 to ILC2 plays an important role in the initiation of adipose fibrosis and onset of obese type 2 diabetes. In this study, based on the existing obese clinical cohort as well as cell sorting system, we aim to clarify the driving role of ILCs in adipose fibrosis and insulin resistance using gene knockout mice, flow cytometry analysis and molecular biological techniques. Also, further studies will be conducted to reveal the response mechanism of immune cells when exposed to environmental stimulus. This study will provide theoretical evidences for new therapeutic targets in treatment strategy of obese type 2 diabetes.

近年发现脂肪组织区域免疫特性紊乱与肥胖代谢病的发生密切相关，其稳态失衡可导致脂肪组织纤维化和炎症反应，但始动机制不明确。最新研究报道，脂肪组织1型固有淋巴细胞（ILC1）异常积聚可驱动M1促炎巨噬细胞极化和胰岛素抵抗，而ILC2则有助于维持M2巨噬细胞区域定植及代谢稳态。我们研究首次发现，肥胖者较对照者网膜脂肪组织ILC1/ILC2细胞和M1/M2巨噬细胞比例升高，脂肪组织纤维化程度加重，且在肥胖2型糖尿病中进一步升高，提示ILC1/ILC2比例失衡相关的免疫失稳在脂肪组织纤维化及肥胖糖尿病中具有重要作用。本课题将基于已建立的肥胖队列和组织单细胞分选系统，借助基因敲除动物模型、流式细胞术及分子生物学方法，阐明ILC1/ILC2稳态失衡在脂肪组织纤维化及胰岛素抵抗中的始动作用及机制，并揭示ILC1/ILC2响应环境应答的分子机制，研究结果有助于为寻找肥胖2型糖尿病的新干预靶点奠定理论基础。

脂肪组织区域免疫特性与脂肪组织功能以及机体代谢稳态密切相关，但其内在联系和作用靶点仍待明确。我们的研究聚焦于固有免疫细胞家族（ILCs），取得了一系列重要突破：（1）首次发现脂肪组织Ⅰ型固有免疫细胞（ILC1s）通过分泌IFN-γ促进M1巨噬细胞极化，诱导脂肪组织纤维化和胰岛素抵抗；阻断脂肪组织ILC1异常积聚可改善肥胖小鼠脂肪组织纤维化和糖代谢损伤。（2）临床肥胖队列研究显示，脂肪组织ILC1水平和外周血ILC1水平显著正相关，外周血ILC1高水平者较ILC1低水平者的T2DM风险增加13倍，外周血ILC1作为脂肪组织ILC1功能的血清学标记物可为肥胖2型糖尿病（T2DM）发病提供风险评估。（3）应用神经介素U激活小鼠内脏脂肪Ⅱ型固有免疫细胞（ILC2s）促进白色脂肪米色化，改善糖耐量异常。上述研究成果首次揭示了脂肪组织新型免疫细胞ILC家族在肥胖驱动T2DM发生中的关键调控作用，提出了ILC1s和ILC2s为防治肥胖T2DM的新分子靶标。本项目资助发表SCI论文16篇，3篇代表性著作发表于Nature Communications 2019（独立通讯，IF=12.121）、Diabetes &Metabolism 2019（最后通讯，IF=4.731）、International Journal of Endocrinology 2021（独立通讯，IF=3.257）。相关研究成果在中华医学会糖尿病学分会等学术会议上进行发言交流。项目执行期间，本团队招收2名博士后，培养了 3名博士研究生和10名硕士研究生。项目负责人获2019年中华医学会糖尿病学分会青年委员会杰出青年科学研究奖，江苏省333高层次人才培养工程第二层次培养对象，南京市最具影响力留学人才。