NLRP3炎性小体在抑郁症和糖尿病共病中的作用及其分子机制

There exists comorbidity of depression and diabetes. Chronic low-grade inflammation is considered to be the common pathophysiology underlying the two diseases. Interliukin-1β (IL-1β) converting enzyme, which is an important component of the NLRP3 inflammasome, regulates the cleavage and maturation of pro-inflammatory cytokine IL-1β and then engages immune and inflammatory responses. Our previous studies showed that NLRP3 inflammasome and IL-1β played the critical role in depression. And there exist defects in insulin secretion and insulin resistance (IR) in chronic unpredictable mild stress (CUMS) induced depressive-like mice. Moreover, antidiabetic drug glyburide significantly alleviated not only IR, but also CUMS induced depressive-like behavior mediated by inhibition of NLRP3 inflammasome activation. It is suggested that the NLRP3 inflammasome activated low-grade inflammation may participate in the pathogenesis and may be the key target of comorbidity of depression and diabetes. Therefore, to investigate the signal pathways and critical role of NLRP3 inflammasome in comorbidity of depression and diabetes from the whole, organ and tissue, cellular and molecular level, we will use NLRP3 knockout mice and CUMS/High fat diet plus streptozotocin induced mice as model. The work may contribute to the understanding of the molecular mechanisms for CUMS induced depression comorbidity of diabetes and HFD+STZ induced diabetes comorbidity of depression, and propose a novel insight into the prevention and treatment of comorbidity of depression and diabetes.

抑郁症与糖尿病高度共病，慢性低活度炎症反应是其共同的病理生理基础。白介素-1β（IL-1β）是重要的炎性细胞因子，其成熟活化需要经过IL-1β转化酶的剪切，而后者是构成炎性小体的核心组分。我们前期研究发现，NLRP3炎性小体和IL-1β在抑郁症发病中起关键性作用，慢性应激诱导的抑郁样小鼠存在胰岛素抵抗及胰岛分泌功能异常，而格列本脲在改善胰岛素抵抗的同时能够通过抑制NLRP3活性显著缓解抑郁样行为，提示以NLRP3激活为核心的慢性低活度炎症反应可能是抑郁症与糖尿病共病的关键靶点。本项目拟利用已有的NLRP3基因敲除小鼠，分别采用CUMS、HFD+STZ方法构建小鼠抑郁与糖尿病共病模型，以炎性小体信号通路为切入点，在整体、组织器官和细胞分子水平，阐明CUMS诱导抑郁共病糖尿病和HFD+STZ诱导糖尿病共病抑郁的分子机制，明确NLRP3在抑郁症与糖尿病共病中的关键性作用，为疾病防治提供新的靶点。

抑郁症与糖尿病高度共病，慢性低活度炎症反应是其共同的病理生理基础。白介素-1β（IL-1β）是重要的炎性细胞因子，其成熟与活化需要经过IL-1β转化酶的剪切，而后者是构成炎性小体的核心组分之一。我们前期研究发现，NLRP3炎性小体和IL-1β在抑郁症发病中起关键性作用，慢性应激在诱导小鼠抑郁样行为的同时导致胰岛素抵抗及胰岛分泌功能异常，应用炎性小体抑制剂可同时改善其抑郁样行为及糖代谢紊乱，提示NLRP3炎性小体可能是糖尿病与抑郁症共病的关键机制。本项目分别采用慢性不可预见性温和应激（CUMS）及腹腔注射链脲菌素（STZ）等方法构建小鼠糖尿病与抑郁共病模型，利用梯度化配制高糖培养基模拟体内高浓度葡萄糖环境，聚焦细胞因子及炎症激活，以NLRP3炎性小体激活相关信号通路为切入点，在整体、组织器官和细胞分子水平开展研究，明确NLRP3炎性小体在共病中的重要作用及具体机制。研究结果表明，慢性应激可以系统性激活NLRP3炎性小体，促进IL-1β等炎性细胞因子释放，诱发小鼠抑郁样行为共病糖代谢紊乱；体内外高浓度葡萄糖环境能够活化炎性小体激活的经典信号通路，激活小胶质细胞NLRP3炎性小体，从而介导糖尿病小鼠的抑郁样行为；NLRP3炎性小体特异性抑制剂（格列本脲、MCC950）可以明显改善复杂应激因素诱发的抑郁症与糖尿病共病。综上，本研究明确了NLRP3在慢性应激诱导糖尿病与抑郁症共病中的关键作用，阐明了其具体分子机制，为共病的防治提供了新思路和新靶点。