類固醇對過敏相關免疫細胞凋亡的影響

Abstract

氣喘是一種由異常的第二型免疫反應引起的呼吸系統過敏性疾病。在氣喘發作時，過敏原或化學毒性分子等會破壞並誘導氣道上皮細胞釋放危險信號。這些元素還可以被固有層中的樹突狀細胞吸收，並促進輔助型T細胞2型（Th2）的生成。除此之外，組織駐留的第二型固有淋巴細胞（ILC2）也可以被危險信號激活，並釋放第二型細胞激素以招募嗜酸性粒細胞、產生黏液和促進平滑肌收縮。皮質類固醇是一種強效的糖皮質激素受體激動劑，用於抗發炎以抑制氣喘發作。儘管如此，這些藥物在臨床治療中會引發強烈的副作用。先前的研究表明，皮質類固醇可以誘導T細胞的凋亡。然而，皮質類固醇誘導的不同免疫細胞亞群的凋亡機制尚未被探討。在此，我們闡明了Dexamethasone調節第二型免疫反應相關風險的機制。首先，我們證明了Dexamethasone可以抑制Th1和Th2細胞中第一型和第二型細胞因子的產生。另外，我們發現，與Th1和Th0細胞相比，Th2細胞可以通過上調Bcl-2抗凋亡基因表達來抵抗Dexamethasone誘導的細胞凋亡現象以啟動抗凋亡反應。另一方面，ILC2仍然是第二型免疫反應中的關鍵淋巴細胞，我們檢測了小鼠肺部中的ILC和ILC2群體，發現ILC2是小鼠肺部中主要的ILC亞群。除此之外，不同性別的小鼠肺部組織駐留的ILC和ILC2也表現出不同的群體分佈。最終，我們發現Dexamethasone可抑制ILC2的二型細胞激素分泌能力，但並未在ILC2中誘導出明顯的凋亡現象。總而言之，第二型免疫細胞對Dexamethasone誘導的細胞凋亡具有抗性，這一現象表明Dexamethasone可能會影響第一型和第二型免疫之間的平衡。

Asthma is an allergic disease caused by abnormal type two immunity in the respiratory system. During the asthma attack, the allergen or chemical toxin sabotages and induces the release of danger signals by airway epithelial cells. These elements can also be taken up by dendritic cells in the lamina propria and promote the generation of T-helper 2 cells (Th2). In addition, tissue-resident type 2 innate lymphoid cells (ILC2) can be activated by danger signals and release type two cytokines for eosinophil recruitment, mucus production, and smooth muscle contraction. Corticosteroids are strong glucocorticoid receptor agonists used for anti-inflammatory purposes to suppress asthma attacks. Still, these medications trigger strong side effects during clinical treatment. Previous studies show that corticosteroids can induce the apoptotic phenomenon in T cells. However, the mechanism of the corticosteroid-induced apoptotic phenomenon in different immune cell subsets remains unexplored. Here, we elucidate the mechanism by which dexamethasone modulates the risks associated with type 2 immune responses. First, we demonstrated that dexamethasone can inhibit both type one and type two cytokine production in Th1 and Th2 cells. In addition, we found that Th2 cells can resist dexamethasone-induced cell apoptosis compared to Th1 and Th0 cells through up-regulating the Bcl-2 anti-apoptotic gene expression to engage the anti-apoptotic response. On the other hand, the ILC2 is still a key lymphocyte for the type 2 immune response, we checked the ILC and ILC2 population in the murine lung and found that ILC2 is a dominant ILC subset in the murine lung. Additionally, the lung-resident ILC and ILC2 present different populations in different genders of the naïve mice. Finally, we found that although dexamethasone could inhibit the type 2 cytokine production of ILC2, it did not induce a significant apoptotic phenomenon on ILC2. In summary, the type 2 immune cells were resistant to dexamethasone-induced cell apoptosis, this phenomenon suggests that the balance between the type 1 and type 2 immunity might impacted by the dexamethasone.