Th22/IL-22在胰岛β细胞炎性损伤及代偿中的双面作用及机制研究

The inflammatory damage triggered by CD4+ T (Th) cells plays critical roles in pancreatic β cell failure in diabetes. Th22 cells, newly identified as a distinct lineage of CD4+ T cells characterized by their production of interleukin-22 (IL-22) and TNFα, is an emergent constitutor in inflammatory diseases. IL-22 exerts its biological effects by binding with IL-22R, which is a heterodimer composed of an IL-10Rβ and an IL-22Rα subunit. It is bi-functional with both pro-inflammatory and proliferative effects on tissues depending on the inflammatory context. Our study first revealed the hyperactivation of Th22 in type 2 diabetic patients and suggested a positive correlation of Th22 with β cell damage. But there is still no literature concerning the exact effects of Th22 on β cell function. Considering that IL-22R is expressed locally in the human pancreatic islets, we primarily testified the effect of IL-22 on a β cell lineage and revealed a double-sided effect of pro-apoptosis and proliferation with or without TNFα. And the cytotoxic effect was dependent on the activation IL-22R-STAT3 pathway. Emerging evidences implied a plausible but controversy role of IL-22R and STAT signaling in β-cell function. And these clues raised questions that whether the increased Th22 is causative/ hazardous or compensatory/ protective factor in β-cell failure. Based on our clinical findings, the present study would utilize the gene knockout mice as well as siRNA transfected cell models to further explore the exact effects of Th22/IL-22 on β cell damage and proliferation as well as its underlying mechanisms, in efforts to provide novel target of β cell preservation and regeneration.

CD4+T细胞介导的炎性损伤在糖尿病β细胞衰竭中扮演关键角色。Th22是Th亚群中的新成员，其关键效应因子包括TNF-α与IL-22，后者的生物学效应可因组织特异性或炎性氛围的差异而截然不同。我们前期在2型糖尿病患者中发现Th22水平上调，并揭示其与β细胞损伤呈显著正相关。其对β细胞有无直接作用尚无报道。而我们预实验发现IL-22对INS-1细胞有促凋亡与促增殖的双面作用，并初步证实其损伤作用依赖IL-22R-STAT3通路。目前有研究侧面提示IL-22R信号及STAT通路可能影响β细胞的损伤或代偿，但存在不少争议。我们推测这正与IL-22在不同条件下作用的双面性有关。故Th22/IL-22对β细胞的直接影响亟待系统论证。本研究通过IL-22R敲基因小鼠及体外转染模型等从系统、器官、细胞三个层面探讨IL-22在β细胞损伤及代偿中的作用及机制，以期为β细胞保护、再生策略提供新靶点。

CD4+T细胞介导的炎性损伤在糖尿病β细胞衰竭中扮演关键角色。Th22是Th亚群中的新成员，其关键效应因子包括TNF-α与IL-22，后者的生物学效应可因组织特异性或炎性氛围的差异而截然不同。我们前期在2型糖尿病患者中发现Th22水平上调，并揭示其与β细胞损伤呈显著正相关。其对β细胞有无直接作用尚无报道。目前有研究侧面提示IL-22R信号及STAT通路可能影响β细胞的损伤或代偿，但存在不少争议。我们推测这正与IL-22在不同条件下作用的双面性有关。故Th22/IL-22对β细胞的直接影响亟待系统论证。本研究通过IL-22R敲基因小鼠及体外转染模型等从系统、器官、细胞三个层面探讨IL-22在β细胞损伤及代偿中的作用及机制，以期为β细胞保护、再生策略提供新靶点。在国家自然科学基金的支持下，本研究：.1.系统验证了IL-22的独立作用和炎症环境下分别对beta细胞增生的影响和对beta细胞细胞毒性作用(凋亡及坏死情况)。系统探讨IL-22作用于beta细胞的具体信号通路机制：IL-22的双向作用与受体亚单位有关（分别由IL-10Ra和IL-22Rb介导），以及不同细胞因子（炎性因子）共同作用下的信号通路变化（STAT3及MAPK两大通路）;此外还发现该过程还与α细胞等旁分泌功能有关，并影响β细胞的去标识化。.2.进一步在人群中探讨了Th22细胞在内的CD4阳性细胞亚群、CD8细胞群等在肥胖、糖尿病及自身免疫性甲状腺疾病中的变化趋势，尤其是在糖尿病人群中Th22细胞极化的转录机制，得到自身免疫紊乱相关内分泌代谢疾病的干预方面的启示。并进一步提出淋巴细胞自体扩增培养后过继输注的治疗策略设想，并在动物模型初步验证，有望改善糖尿病免疫炎症紊乱状态，改善β细胞功能进而延缓糖尿病并发症的发生发展。