ATP6V0d2 Suppresses Alveoli Macrophage Alternative Polarization and Allergic Asthma via Degradation of PU.1

Na Liu; Yuchen Feng; Huicheng Liu; Wenliang Wu; Yuxia Liang; Pingfei Li; Zhengping Wei; Min Wu; Zhao Hui Tang; Junyan Han; Xiang Cheng; Zheng Liu; Arian Laurence; Huabin Li; Guohua Zhen; Xiang Ping Yang

doi:10.4168/aair.2021.13.3.479

ATP6V0d2 Suppresses Alveoli Macrophage Alternative Polarization and Allergic Asthma via Degradation of PU.1

Allergy Asthma Immunol Res. 2021 May;13(3):479-497. doi: 10.4168/aair.2021.13.3.479.

Authors

Na Liu^#^{1

2}, Yuchen Feng^#³, Huicheng Liu¹, Wenliang Wu³, Yuxia Liang³, Pingfei Li¹, Zhengping Wei¹, Min Wu¹, Zhao Hui Tang⁴, Junyan Han¹, Xiang Cheng⁵, Zheng Liu⁶, Arian Laurence⁷, Huabin Li⁸, Guohua Zhen³, Xiang Ping Yang^{1

9}

Affiliations

¹ Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
² Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
⁴ Department of Surgery, Tongji Hospital, Huazhong University of Science and Technology (HUST), Wuhan, China.
⁵ Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
⁶ Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology (HUST), Wuhan, China.
⁷ University College Hospital, NHS Trust, London, United Kingdom.
⁸ Department of Otolaryngology, Head and Neck Surgery, Affiliated Eye-Ear-Nose and Throat Hospital, Fudan University, Shanghai, China.
⁹ Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. yangxp@hust.edu.cn.

^# Contributed equally.

Abstract

Purpose: 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.

Methods: We compared the disease severity between female C57BL/6 wild-type and ATP6V0d2^-/- mice in an ovalbumin (OVA)-induced asthma model. We also investigated the association of expression of ATP6V0d2, PU.1 and CCL17 with disease severity among asthmatic patients.

Results: The expression of ATP6V0d2 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, ATP6V0d2-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, ATP6V0d2 expression was inversely associated with disease severity, whereas PU.1 and CCL17 expression was positively associated with disease severity.

Conclusions: 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.

Keywords: Asthma; Pu.1 protein; V-type ATPase; alveolar macrophage.

Abstract

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