USP22/BRD4介导的Hedgehog信号通路激活促进哮喘气道重塑
2025/04/30
摘要
背景：含溴结构域蛋白4（BRD4）作为溴结构域和超末端结构域（BET）家族成员，参与哮喘气道炎症及气道重塑过程，但其在气道平滑肌细胞（ASMCs）增殖和气道重塑中的具体机制尚未阐明。
方法：本研究采用原代培养大鼠ASMCs及卵清蛋白（OVA）诱导的大鼠哮喘模型，探究BRD4的功能机制。
结果：转化生长因子β1（TGF-β1）通过上调泛素特异性肽酶22（USP22）蛋白表达，介导BRD4的去泛素化修饰从而促进其表达，进而激活神经胶质瘤相关癌基因同源蛋白1（GLI1）和骨桥蛋白（OPN），最终导致ASMCs异常增殖。在OVA诱导的哮喘模型中，TGF-β1/USP22/BRD4/GLI1/OPN信号轴级联激活驱动气道重塑，靶向抑制该通路可显著缓解气道重塑及哮喘进展。
结论：本研究揭示了TGF-β1/USP22/BRD4/GLI1/OPN信号轴在哮喘气道重塑中的关键作用，提示靶向干预该通路可能为哮喘防治提供新策略。
USP22/BRD4 mediated hedgehog pathway activation contributes to airway remodeling in asthma
H. Chen, J. Liu, J. Zhang, Y. Q. Chen, Y. Wang, Y. J. Qiu, et al.
Abstract
BACKGROUND:Bromodomain-containing protein 4 (BRD4) is recognized as a member of the bromodomain and extraterminal (BET) family that is involved in the airway inflammation and airway remodeling of asthma. However, the underlying mechanisms of BRD4 in airway smooth muscle cells (ASMCs) proliferation and airway remodeling remain unclear.
METHODS:Primary cultured rat ASMCs and ovalbumin (OVA)-induced rat asthma models were applied to address these issues in the present study.
RESULTS: We showed that transforming growth factor β1 (TGF-β1) increased the protein expression of ubiquitin specific peptidase 22 (USP22), which deubiquitinated BRD4 therefore increased its expression, and then resulted in the upregulation of glioma-associated oncogene homolog 1 (GLI1) and osteopontin (OPN) leading to ASMCs proliferation. We further confirmed that induction of TGF-β1 sequentially upregulated USP22, BRD4, GLI1 and OPN leading to airway remodeling in OVA-induced rat asthma models, targeting TGF-β1/USP22/BRD4/GLI1/OPN pathway axis effectively attenuated airway remodeling and asthma development.
CONCLUSION:Our study provides novel sights to understand the role of TGF-β1/USP22/BRD4/GLI1/OPN axis in airway remodeling, and targeting this pathway might have potential value for the prevention and treatment of asthma.
背景：含溴结构域蛋白4（BRD4）作为溴结构域和超末端结构域（BET）家族成员，参与哮喘气道炎症及气道重塑过程，但其在气道平滑肌细胞（ASMCs）增殖和气道重塑中的具体机制尚未阐明。
方法：本研究采用原代培养大鼠ASMCs及卵清蛋白（OVA）诱导的大鼠哮喘模型，探究BRD4的功能机制。
结果：转化生长因子β1（TGF-β1）通过上调泛素特异性肽酶22（USP22）蛋白表达，介导BRD4的去泛素化修饰从而促进其表达，进而激活神经胶质瘤相关癌基因同源蛋白1（GLI1）和骨桥蛋白（OPN），最终导致ASMCs异常增殖。在OVA诱导的哮喘模型中，TGF-β1/USP22/BRD4/GLI1/OPN信号轴级联激活驱动气道重塑，靶向抑制该通路可显著缓解气道重塑及哮喘进展。
结论：本研究揭示了TGF-β1/USP22/BRD4/GLI1/OPN信号轴在哮喘气道重塑中的关键作用，提示靶向干预该通路可能为哮喘防治提供新策略。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（International Immunopharmacology 2025 Vol. 153 DOI：ARTN 11453810.1016/j.intimp.2025.114538）
USP22/BRD4 mediated hedgehog pathway activation contributes to airway remodeling in asthma
H. Chen, J. Liu, J. Zhang, Y. Q. Chen, Y. Wang, Y. J. Qiu, et al.
Abstract
BACKGROUND:Bromodomain-containing protein 4 (BRD4) is recognized as a member of the bromodomain and extraterminal (BET) family that is involved in the airway inflammation and airway remodeling of asthma. However, the underlying mechanisms of BRD4 in airway smooth muscle cells (ASMCs) proliferation and airway remodeling remain unclear.
METHODS:Primary cultured rat ASMCs and ovalbumin (OVA)-induced rat asthma models were applied to address these issues in the present study.
RESULTS: We showed that transforming growth factor β1 (TGF-β1) increased the protein expression of ubiquitin specific peptidase 22 (USP22), which deubiquitinated BRD4 therefore increased its expression, and then resulted in the upregulation of glioma-associated oncogene homolog 1 (GLI1) and osteopontin (OPN) leading to ASMCs proliferation. We further confirmed that induction of TGF-β1 sequentially upregulated USP22, BRD4, GLI1 and OPN leading to airway remodeling in OVA-induced rat asthma models, targeting TGF-β1/USP22/BRD4/GLI1/OPN pathway axis effectively attenuated airway remodeling and asthma development.
CONCLUSION:Our study provides novel sights to understand the role of TGF-β1/USP22/BRD4/GLI1/OPN axis in airway remodeling, and targeting this pathway might have potential value for the prevention and treatment of asthma.
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