USP4 is pathogenic in allergic airway inflammation by inhibiting regulatory T cell response.

Abstract

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 μg ovalbumin (OVA) mixed in 2 mg aluminum hydroxide in 1 × PBS on days 0, 7 and 14. On days 21 to 27, the mice were challenged with aerosolized 1% OVA in 1 × 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 OVA-challenged 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 allergen-induced murine asthma, and Vialinin A treatment alleviates asthma pathogenesis and may serve as a promising therapeutic target for asthma.

• Authors: Xiaoxia Hou, Fangming Zhu, Yingmeng Ni, Tiantian Chen, Juan Du, Xinnan Liu, Yichao Han, Yahui Liu, Wei Du, Yangyang Li, Xiaoxia Wang, Dan Li, Rui Liang, Bin Li, Guochao Shi
• Journal: Life sciences (Life Sci) Vol. 281 Pg. 119720 (Sep 15 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 34144056 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Usp4 protein, mouse
• Ubiquitin-Specific Proteases

Topics

• Animals
• Asthma (immunology)
• Bronchoalveolar Lavage Fluid
• Cell Differentiation
• Disease Models, Animal
• Female
• Mice
• Mice, Knockout
• T-Lymphocytes, Regulatory (cytology, immunology)
• Ubiquitin-Specific Proteases (genetics, immunology)