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Published on: October 22, 2019
ATP6V0d2 Suppresses Alveoli Macrophage Alternative Polarization and Allergic Asthma via Degradation of PU.1
Na Liu1,2, Yuchen Feng3, Huicheng Liu1
1Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
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.
Insights
Macrophage ATP6V0d2 acts as a protective factor in asthma by reducing inflammation and mucus. Its deficiency worsens allergic asthma symptoms, highlighting its role in regulating airway inflammation.
Area of Science:
- Immunology
- Respiratory Medicine
- Molecular Biology
Background:
- Macrophages play a key role in allergic asthma pathogenesis.
- ATP6V0d2, a vacuolar ATPase subunit, is highly expressed in macrophages, but its function in asthma is unknown.
Purpose of the Study:
- To investigate the role and molecular mechanisms of macrophage ATP6V0d2 in allergic asthma.
- To determine if ATP6V0d2 influences airway inflammation, macrophage polarization, and mucus production.
Main Methods:
- Comparison of disease severity in wild-type versus ATP6V0d2-deficient mice using an ovalbumin-induced asthma model.
- Analysis of ATP6V0d2, PU.1, and CCL17 expression in asthmatic patients and mouse models.
Main Results:
- ATP6V0d2 expression was elevated in asthmatic patients and OVA-challenged mice.
- ATP6V0d2 deficiency exacerbated inflammation, alternative activated macrophage (AAM) polarization, and mucus production in asthma models.
- ATP6V0d2 promotes lysosomal degradation of PU.1, reducing AAM polarization and CCL17 production.
Conclusions:
- Macrophage ATP6V0d2 acts as an induced feedback inhibitor of asthma severity.
- ATP6V0d2 reduces asthma severity by promoting PU.1 degradation, leading to decreased AAM polarization and CCL17 production.
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