TIPE2通过促进巨噬细胞M2极化缓解哮喘的效应及其分子机制

Asthma is the most common chronic respiratory disease in children. Repeated attacks affect the quality of life and medical expenditure. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) is a negative regulator of innate and acquired immune response. TIPE2 expression reduced in asthmatic children. Our previous studies showed that TIPE2 inhibited macrophage M1 polarization induced by IFN-γ/LPS and inhibited the production of proinflammatory cytokine TNF-α and IL-6.TIPE2 promoted M2 polarization induced by IL-4 and the production of anti-inflammatory cytokine IL-10, and enhanced Akt phosphorylation, but did not affect the phosphorylation of STAT6. In combination with previous studies and related literatures, we suggest a hypothesis that TIPE2 can promote M2 polarization of macrophages through PI3K/Akt signaling pathway and then alleviate asthma.This project will study the effect of TIPE2 on asthma and macrophage polarization by using mice with TIPE2 conditional knockout and mice with TIPE2 overexpression and explore the molecular mechanism of TIPE2 promoting M2 polarization of macrophages. The results will provide a new understanding of the immunoregulation mechanism of asthma, and may provide new candidate targets for the drugs of asthma.

支气管哮喘是儿童最常见慢性呼吸道疾病，反复发作影响生活质量及医疗支出。TIPE2是天然免疫和获得性免疫反应负向调控因子，哮喘儿童TIPE2下调。我们前期研究发现TIPE2可抑制IFN-γ/LPS诱导的巨噬细胞M1极化及促炎细胞因子TNF-α、IL-6的产生；促进IL-4诱导的巨噬细胞M2极化及抗炎细胞因子IL-10的产生，增强Akt磷酸化，不影响STAT6磷酸化。结合前期研究和相关文献，我们提出TIPE2可通过PI3K/Akt信号通路促进巨噬细胞M2极化并缓解哮喘。本项目拟利用TIPE2条件性敲除和过表达小鼠研究TIPE2对哮喘的调控作用及对巨噬细胞极化的影响，通过沉默或过表达实验、免疫共沉淀和GST pull-down实验探索其如何参与信号通路的调控，深入揭示TIPE2促进巨噬细胞M2极化的分子机制。研究结果可为哮喘免疫调控机制提供新的认识，并为研发治疗哮喘药物提供新的候选靶分子。

巨噬细胞作为免疫细胞，在机体免疫防御反应中起重要作用，在疾病中的作用越来越受到关注。巨噬细胞在不同的环境中可活化为M1型巨噬细胞或M2型巨噬细胞，发挥不同的生物功能。LPS可诱导巨噬细胞向M1极化，IL-4、IL-13可诱导巨噬细胞向M2极化。巨噬细胞极化和哮喘、急性肺损伤关系密切，探索巨噬细胞极化与哮喘、急性肺损伤的关系可为疾病的治疗提供新的思路。我们发现哮喘小鼠肺巨噬细胞M2极化增强、IL-4升高，TIPE2能促进IL-4诱导的小鼠骨髓来源巨噬细胞M2极化、促进IL-10产生，提示TIPE2可能通过调控巨噬细胞极化进而调控哮喘。我们还发现TSP2可抑制LPS诱导的小鼠肺泡巨噬细胞MH-S细胞M1极化并通过活化PI3K/AKT信号通路诱导其向M2极化，TSP2还能缓解LPS诱导的小鼠急性肺损伤并抑制巨噬细胞M1极化、促进M2极化，提示TSP2可能通过PI3K/AKT信号通路调控巨噬细胞极化进而缓解LPS诱导的急性肺损伤。我们还探索了中药提取物欧前胡素对LPS诱导的巨噬细胞活化的影响，发现欧前胡素能通过NF-κB信号通路抑制LPS诱导的小鼠骨髓来源巨噬细胞活化。本项目研究结果为哮喘及急性肺损伤的新治疗提供了理论基础。