USP4 is Pathogenic in Allergic Airway Inflammation by Inhibiting Regulatory T Cell Response.
Life sciences(2021)
摘要
Aims: Asthma is characterized by chronic inflammation and airway hyperresponsiveness (AHR). It is controllable, but not curable. Ubiquitin-specific peptidase 4 (USP4) has been verified as a regulator of regulatory T (Treg) cells and Th17 cells in vitro. In this study, we aim to investigate whether USP4 could serve as a therapeutic target for asthma. Main methods: Age-matched USP4 wild-type and knockout mice received an intraperitoneal injection of 100 mu g ovalbumin (OVA) mixed in 2 mg aluminum hydroxide in 1 x PBS on days 0, 7 and 14. On days 21 to 27, the mice were challenged with aerosolized 1% OVA in 1 x PBS for 30 min. Tissue histology, ELISA and flow cytometry were applied 24 h after the last OVA challenge. Key findings: USP4 deficiency protected mice from OVA-induced AHR and decreased the production of several inflammatory cytokines in T cells in vivo. Compared to the lung cells isolated from WT mice, Usp4-/- lung cells decreased secretion of IL-4, IL-13 and IL-17A upon stimulation in vitro. Meanwhile, the percentage of CD4+Foxp3+ Treg cells was elevated, with more CCR6+Foxp3+ Treg cells accumulating in the lungs of OVAchallenged USP4 deficient mice than in their wild-type counterparts. Treatment with the USP4 inhibitor, Vialinin A, reduced inflammatory cell infiltration in the lungs of OVA-challenged mice in vivo. Significance: We found USP4 deficiency contributes to attenuated airway inflammation and AHR in allergeninduced murine asthma, and Vialinin A treatment alleviates asthma pathogenesis and may serve as a promising therapeutic target for asthma.
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关键词
Ubiquitin-specific protease 4 (USP4),Asthma,Regulatory T cell (Treg cell),C-C motif chemokine receptor 6 (CCR6),USP4 inhibitor
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