调节蛋白Trim33调控肺脏巨噬/树突状细胞发育及肺脏炎症性疾病免疫应答机制研究

Inflammatory lung diseases, such as interstitial pulmonary fibrosis and asthma, are life-threatening diseases and are refractory to treatment. Thus, better understanding of the molecular and cellular mechanisms of these diseases is critical for developing new therapeutic strategies. Alveolar macrophages (AMs) and lung resident dendritic cells (DCs) play crucial roles in maintaining the balance of lung immune homeostasis and regulating the immune response of inflammatory lung disease. Although accumulating evidence demonstrated that the development of AMs and DCs is regulated by different transcriptional factors and cytokines, the mechanisms about how their development were precisely regulated in lung remains uncertain. Tripartite motif-containing protein 33 (Trim33) is a multi-functional protein, which is involved in a lot of physiology and pathology processes via regulating the transcription of different genes or the stable of proteins by acting as ubiquitin enzymes. Trim33 is documented to be involved in the development of hematopoietic stem cells and the activation of immune cells such as macrophages, raising its possible role in regulating the development and function of AMs and DCs. Herein, we focus on exploring the role of Trim33 on the development and function of AMs and lung resident DCs and its role in regulating the immune responses in inflammatory lung diseases. Our study could provide some support on exploring new therapeutic strategies for inflammatory lung diseases by targeting on the key downstream factors regulated by Trim33.

肺部疾病严重威胁人类健康，临床上治疗方法有限，深入探究此类疾病发病机制对开发潜在治疗靶点尤为重要。肺泡巨噬细胞（Alveolar macrophages, AMs）和肺部常驻树突状细胞（Dendritic cells, DCs）在肺部免疫稳态维持与炎症性肺病免疫应答中至关重要。AMs和DCs的正常发育是其发挥功能的前提。目前对肺部AMs和DCs的发育调控机制知之甚少，各类细胞的发育调控因子如何精确地发挥调控功能，仍然有待深入探究。Tripartite基序蛋白33（Tripartite motif-containing protein 33, Trim33）是一种多功能蛋白，参与多种生理病理过程，研究提示Trim33可能参与造血干细胞发育及免疫细胞功能调控。本研究旨在探究Trim33参与调控肺泡巨噬细胞及肺部常驻树突状细胞发育及功能的新机制，以期为肺部疾病的防治提供新的靶点。

过敏性哮喘是一类常见的慢性气道炎症，临床治疗手段有限。肺泡巨噬细胞(Alveolar macrophages, AMs)和树突状细胞(Dendritic cells, DCs)是肺脏黏膜主要的固有免疫细胞，在过敏性哮喘的发病过程中发挥重要作用。因此，探究AMs及DCs的功能调控分子，对于阐明哮喘的发病机制及挖掘潜在治疗靶点至关重要。Tripartite基序蛋白33（Tripartite motif-containing protein 33, TRIM33）是一种多功能蛋白，参与多种生理和病理过程。然而，TRIM33是否调控AMs及肺部常驻DCs的发育及功能，及是否参与调控过敏性哮喘相关免疫应答尚不清楚。本研究发现，利用条件性敲除小鼠（ItgaxCreTrim33fl/fl）特异性敲除TRIM33能够显著下调AMs及肺部常驻DCs的数目，提示TRIM33对这两类细胞的稳态维持非常关键。此外，建立户尘螨（House dust mites, HDM）诱导的过敏性哮喘小鼠结果发现，AMs和DCs特异性TRIM33缺陷会导致HDM诱导的过敏性哮喘加重，表现为加重的肺组织局部嗜酸性粒细胞气道炎症及Th2应答。回输野生型AMs能够显著缓解ItgaxCreTrim33fl/fl小鼠中加重的过敏性哮喘表型。进一步研究发现， TRIM33缺陷的AMs在过敏原刺激后活化水平上调，表达更高水平的趋化因子CCL2，可能通过调控炎性CD11b+DCs向肺部及淋巴结的浸润，促进其诱导的Th2应答，最终导致激发期哮喘相关气道炎症及Th2免疫应答的增强。本研究提示，TRIM33不仅参与肺部AMs和DCs的稳态维持，同时，能够作为一个分子开关，调控哮喘发病过程中AMs的功能，控制哮喘相关免疫应答强度。