炎性肠病中富亮氨酸重复激酶2对树突细胞迁移的作用及其机制

Inflammatory bowel disease(IBD) is a common chronic intestinal inflammation syndrome, and abnormal immune responses are involved in its pathology. Dendritic cells(DCs) are antigen-presenting cells and considered as the first step of immune responses.However,whether the altered migration capacity of DC and its mechanism are involved in IBD remains elusive. LRRK2 is recently found to be related to the pathology of IBD. We for the first time found that LRRK2 defects facilitates intracellular calcium concentration in DCs through Store-operated calcium channel(SOCC). Our previous data showed the enhanced DCs migration and SOCE in IBD. Moreover, we already published a paper about the relationship between LRRK2 and SOCC in DCs. Given the importance of intracellular calcium concentration in the migration of DC, we propose that LRRK2 could regulate the migratory capacity via SOCC hence contributing to IBD. In the present study we aim to confirm our hypothesis in DSS-induced IBD model and LRRK2 KO mouse by the utilization of calcium imaging, patch clamp, biochemistry techniques.

炎性肠病是一种慢性非特异性肠道炎症性疾病，普遍认为免疫反应过激是致病因素之一。树突状细胞作为免疫反应的抗原呈递细胞，是免疫反应的启动者。然而对于树突状细胞在肠炎中迁移能力的变化及其机制却还不十分明确。富亮氨酸重复序列激酶2（LRRK2)是近期发现的肠炎的敏感基因，我们以前的研究发现LRRK2能调控树突状细胞(DC)内的钙池操控性钙通道，从而影响细胞内钙浓度。我们的前期结果表明：（1）肠炎模型中DC的迁移能力增加。（2）肠炎模型中DC内钙池操控性钙通道活性升高。（3）LRRK2的缺失使钙池操控性钙通道活性升高。细胞的迁移功能是依赖于钙离子浓度，我们认为LRRK2能通过调控钙池操控性钙通道影响DC迁移能力，从而参与炎性肠病的发病。本研究拟通过钙成像，膜片钳，分子生物学等试验，利用DSS诱导的肠炎模型小鼠和LRRK2敲除小鼠为模型，对此假说进行进一步验证。

溃疡性结肠炎是炎性肠病的一种，多发于结直肠，病因复杂，包括环境，基因，饮食等。富亮氨酸重复激酶2是帕金森的易感基因，其激酶活性的增加是导致脑神经元损伤的主要因素。研究发现富亮氨酸重复激酶2还能够影响肠炎的发生发展，但具体作用机制不明。在溃疡性结肠炎中，我们证实通过提高不成熟树突细胞的迁移，抑制巨噬细胞的促炎功能，能够快速缓解炎症，抑制过度炎症导致的组织损伤。我们发现富亮氨酸重复激酶2在小鼠髓系树突细胞内高表达，它的缺失会促进不成熟状态的树突细胞过度迁移，从而介导免疫耐受。通过单细胞测序我们还发现富亮氨酸重复激酶2缺失抑制了髓系巨噬细胞的促炎功能，并且和免疫细胞招募相关，能够重塑微环境，影响炎症的发展，调控炎症向肿瘤发展的过程, 因此富亮氨酸重复激酶2是炎性肠病的行之有效的治疗靶点。

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