Tang Yao, Zhao Yan, Guan Yuanyuan, Xue Longge, Guo Jingsong, Zhao Tingrui, Guan Yuqing, Tong Songlin, Che Chunli
Department of Allergy, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China; Department of Internal Medicine, Harbin Medical University, Harbin, PR China; NHC Key Laboratory of Cell Transplantation, Harbin, PR China.
Department of Allergy, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China.
Immunol Lett. 2024 Dec;270:106923. doi: 10.1016/j.imlet.2024.106923. Epub 2024 Sep 10.
Allergic asthma is a primary type of asthma and characterized by T helper 2 (Th2) cells -mediated inflammation. Tripartite motif containing 8 (TRIM8) protein is involved in immunoreaction and inflammatory response in many diseases. However, its role in allergic asthma remains unclear. Medical databank showed that TRIM8 was increased in lung of ovalbumin (OVA)-challenged mice. This study aimed to elucidate the effects of TRIM8 on allergic asthma and Th2 development.
Asthma were induced by OVA challenge in mice, and the adenovirus vector loaded with TRIM8 knockdown sequence was delivered into asthma mice by nasal inhalation. The percentage of Th2 cells in lung was assessed by flow cytometric analysis, and the contents of Th2 cytokines (interleukin (IL)-4, IL-5 and IL-13) in bronchoalveolar lavage fluid (BALF) were assessed with ELISA. In vitro Th2 induction was performed in CD4 cells from mouse spleen, the expression of Th2 molecules (IL-4, IL-5 and GATA binding protein 3 (GATA3)) were measured by real-time PCR. In addition, the nuclear factor-kappa B (NF-κB)/nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) signaling was determined.
TRIM8 was highly expressed in the lung tissues of asthmatic mice and Th2-induced CD4 cells. OVA challenge-induced Th2 development and Th2 cytokine secretion were restrained by silencing of TRIM8 in vivo. Similarly, the Th2 differentiation in vitro was also suppressed by TRIM8 knockdown. TRIM8 inhibited the NF-κB/NLRP3 activity by blocking transforming growth factor-beta-activated kinase 1 (TAK1), and the effects of TRIM8 were abrogated by overexpression of NLRP3.
Silencing TRIM8 relieved the asthmatic injury in mice and excessive Th2 development via inhibiting the NF-κB/NLRP3 pathway. It is indicated that TRIM8 may contribute to the airway inflammation in allergic asthma via activating the NF-κB/NLRP3 signaling pathway. The current study provided a novel potential target for allergic asthma treatment.
过敏性哮喘是哮喘的主要类型，其特征为辅助性T细胞2（Th2）介导的炎症反应。含三联基序蛋白8（TRIM8）参与多种疾病的免疫反应和炎症反应。然而，其在过敏性哮喘中的作用尚不清楚。医学数据库显示，在卵清蛋白（OVA）攻击的小鼠肺组织中TRIM8表达增加。本研究旨在阐明TRIM8对过敏性哮喘和Th2细胞发育的影响。
通过OVA攻击诱导小鼠哮喘模型，将携带TRIM8基因敲低序列的腺病毒载体经鼻吸入导入哮喘小鼠体内。采用流式细胞术分析肺组织中Th2细胞百分比，用酶联免疫吸附测定法（ELISA）检测支气管肺泡灌洗液（BALF）中Th2细胞因子（白细胞介素（IL）-4、IL-5和IL-13）含量。体外从小鼠脾脏CD4细胞诱导Th2细胞，用实时聚合酶链反应（PCR）检测Th2相关分子（IL-4、IL-5和GATA结合蛋白3（GATA3））的表达。此外，检测核因子κB（NF-κB）/核苷酸结合寡聚化结构域、富含亮氨酸重复序列和含pyrin结构域蛋白3（NLRP3）信号通路。
TRIM8在哮喘小鼠肺组织和Th2诱导的CD4细胞中高表达。体内敲低TRIM8可抑制OVA攻击诱导的Th2细胞发育和Th2细胞因子分泌。同样，体外敲低TRIM8也可抑制Th2细胞分化。TRIM8通过阻断转化生长因子-β激活激酶1（TAK1）抑制NF-κB/NLRP3活性，过表达NLRP3可消除TRIM8的作用。
敲低TRIM8可通过抑制NF-κB/NLRP3信号通路减轻小鼠哮喘损伤和Th2细胞过度发育。提示TRIM8可能通过激活NF-κB/NLRP3信号通路参与过敏性哮喘气道炎症反应。本研究为过敏性哮喘治疗提供了一个新的潜在靶点。
