Liu Na, Feng Yuchen, Liu Huicheng, Wu Wenliang, Liang Yuxia, Li Pingfei, Wei Zhengping, Wu Min, Tang Zhao Hui, Han Junyan, Cheng Xiang, Liu Zheng, Laurence Arian, Li Huabin, Zhen Guohua, Yang Xiang Ping
Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Allergy Asthma Immunol Res. 2021 May;13(3):479-497. doi: 10.4168/aair.2021.13.3.479.
Macrophages are important regulators of environmental allergen-induced airway inflammation and asthma. ATP6V0d2 is a subunit of vacuolar ATPase highly expressed in macrophages. However, the functions of ATP6V0d2 in the regulation of pathogenesis of allergic asthma remain unclear. The aim of this study is to determine the function and related molecular mechanisms of macrophage protein ATP6V0d2 in allergic asthma.
We compared the disease severity between female C57BL/6 wild-type and mice in an ovalbumin (OVA)-induced asthma model. We also investigated the association of expression of , and with disease severity among asthmatic patients.
The expression of in sputum cells of asthmatic patients and in the lungs of OVA-challenged mice was enhanced compared to healthy subjects and their counterparts, respectively. However, -deficient mice exaggerated inflammatory cell infiltration as well as enhanced alternative activated macrophage (AAM) polarization and mucus production in an OVA-induced asthma model. Furthermore, we found that Atp6v0d2 promoted lysosomal degradation of Pu.1, which induced AAM polarization and Ccl17 production. Among asthma patients, expression was inversely associated with disease severity, whereas and expression was positively associated with disease severity.
Our results identify macrophage Atp6v0d2, as an induced feedback inhibitor of asthma disease severity by promoting Pu.1 lysosomal degradation, which may in turn leads to reduced AAM polarization and Ccl17 production.
巨噬细胞是环境变应原诱导的气道炎症和哮喘的重要调节因子。ATP6V0d2是液泡ATP酶的一个亚基，在巨噬细胞中高度表达。然而，ATP6V0d2在过敏性哮喘发病机制调节中的功能仍不清楚。本研究的目的是确定巨噬细胞蛋白ATP6V0d2在过敏性哮喘中的功能及相关分子机制。
我们比较了雌性C57BL/6野生型小鼠和卵清蛋白（OVA）诱导的哮喘模型中的疾病严重程度。我们还研究了哮喘患者中ATP6V0d2、Pu.1和Ccl17的表达与疾病严重程度之间的关联。
与健康受试者及其对应物相比，哮喘患者痰细胞中ATP6V0d2的表达以及OVA激发小鼠肺中的表达分别增强。然而，在OVA诱导的哮喘模型中，ATP6V0d2缺陷小鼠加剧了炎症细胞浸润，并增强了替代性活化巨噬细胞（AAM）极化和黏液分泌。此外，我们发现Atp6v0d2促进了Pu.1的溶酶体降解，从而诱导AAM极化和Ccl17产生。在哮喘患者中，ATP6V0d2的表达与疾病严重程度呈负相关，而Pu.1和Ccl17的表达与疾病严重程度呈正相关。
我们的结果表明，巨噬细胞Atp6v0d2通过促进Pu.1的溶酶体降解，作为哮喘疾病严重程度的诱导性反馈抑制剂，这可能反过来导致AAM极化和Ccl17产生减少。
