局部温热通过STIM1/CRAC钙通道介导Ca2+/Nrf2/NLRP3促进巨噬细胞向M1亚型极化治疗孢子丝菌病的作用机制

孢子丝菌病是孢子丝菌复合体引起的慢性肉芽肿性真菌感染性疾病，其治疗方法是亟待解决的重要科学问题。我们前期发现孢子丝菌病患者皮损中巨噬细胞以抗炎型M2型为主，而局部温热可激活巨噬细胞CRAC钙通道，促进巨噬细胞向促炎型M1型极化从而促进孢子丝菌杀灭，但作用机制尚不清楚。因此我们提出假说：温热通过激活STIM1开启CRAC钙通道，增加细胞内Ca2+，通过Nrf2调控NLRP3炎性小体活化，促进巨噬细胞向促炎的M1型极化；同时，Nrf2又可促进STIM1的表达形成正反馈环，进一步诱导巨噬细胞向M1型极化，最终促进孢子丝菌杀灭。本研究将从细胞、动物和临床标本三个层面探究局部温热通过促巨噬细胞向M1型极化治疗孢子丝菌病的作用及其通过STIM1/CRAC钙通道介导Ca2+/Nrf2/NLRP3促进巨噬细胞向M1型极化杀灭孢子丝菌的作用机制，旨为孢子丝菌病治疗靶点和方法的探寻奠定新的理论与实践基础。

Sporotrichosis is a chronic granulomatous mycosis caused by sporothrix complex. The course of sporotrichosis is always prolonged and even life-threatening, the treatment of this disease in an important scientific problem to be solved. We previously found the predominance of subtype M2 macrophage which play an anti-inflammatory role in the lesions of sporotrichosis, the predominance of M2 macrophage may be responsible for the persistence of sporotrichosis; we also found that local hyperthermia is effective in the treatment of sporotrichosis and hyperthermia treatment can activate the CRAC calcium channel in macrophages which triggers pro-inflammatory type M1 polarization and subsequent killing of sporothrix, however, the mechanism still calls for further investigation. We hypothesize that hyperthermia leads to the activation of CRAC channels resulting in profound Ca2+ influx and Ca2+ upregulates NLRP3 inflammasome expression through inducing Nrf2 activation, then NLRP3 overexpression triggers M1 polarization and subsequent killing of sporothrix. Furthermore, the activation of Nrf2 upregulates STIM1 expression which forms a positive feedback for M1 type polarization of macrophages and further subsequent killing of sporothrix. The purpose of this project is to identify the hypothesis that hyperthermia could treat sporotrichosis by promoting pro-inflammatory type M1 polarization in macrophages, the mechanism by which hyperthermia could treat sporotrichosis is local hyperthermia could led to STIM1/CRAC calcium channel activation mediated calcium ions/Nrf2/NLRP3 induced M1 macrophages polarization and subsequent killing of sporothrix. Our hypothesis will be identified at the cellular level, at the animal model level and at the clinical specimens level. We believe that our project will guide the application of hyperthermia in the treatment of sporotrichosis and provide a new basis of theory and practice after we achieving these goals.