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

Allergy, Asthma & Immunology Research : AAIR 2021년 13권 3호 p.479 ~ 497
Liu Na, Feng Yuchen, Liu Huicheng, Wu Wenliang, Liang Yuxia, Li Pingfei, Wei Zhengping, Wu Min, Han Junyan, Yang Xiang-Ping,
소속 상세정보
 ( Liu Na ) - Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine Department of Immunology
 ( Feng Yuchen ) - Huazhong University of Science and Technology Tongji Medical College Tongji Hospital Department of Internal Medicine
 ( Liu Huicheng ) - Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine Department of Immunology
 ( Wu Wenliang ) - Huazhong University of Science and Technology Tongji Medical College Tongji Hospital Department of Internal Medicine
 ( Liang Yuxia ) - Huazhong University of Science and Technology Tongji Medical College Tongji Hospital Department of Internal Medicine
 ( Li Pingfei ) - Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine Department of Immunology
 ( Wei Zhengping ) - Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine Department of Immunology
 ( Wu Min ) - Huazhong University of Science and Technology Tongji Hospital Department of Surgery
 ( Han Junyan ) - Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine Department of Immunology
 ( Yang Xiang-Ping ) - Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine Department of Immunology

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.

키워드

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

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