Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma

Meixuan Liu,1,2 Mengtian Shan,1 Yunxuan Zhang,3 Zhongliang Guo1,2 1Department of Respiratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, People’s Republic of China; 2Department of Respiratory Medicine, Shanghai East Clinical Medical College, Nanjing Med...

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Autores principales:	Liu M, Shan M, Zhang Y, Guo Z
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	house dust mite-induced asthma airway remodeling progranulin autophagy hmgb1 Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/e0d00c64a40f4ed6a2adaeb5b210bb9a
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spelling	oai:doaj.org-article:e0d00c64a40f4ed6a2adaeb5b210bb9a2021-12-02T17:08:00ZProgranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma1178-7031https://doaj.org/article/e0d00c64a40f4ed6a2adaeb5b210bb9a2021-08-01T00:00:00Zhttps://www.dovepress.com/progranulin-protects-against-airway-remodeling-through-the-modulation--peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Meixuan Liu,1,2 Mengtian Shan,1 Yunxuan Zhang,3 Zhongliang Guo1,2 1Department of Respiratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, People’s Republic of China; 2Department of Respiratory Medicine, Shanghai East Clinical Medical College, Nanjing Medical University, Shanghai, 200123, People’s Republic of China; 3Department of Pharmacy, Huadong Hospital, Fudan University, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Zhongliang Guo Tel +86 18901681968Email drguozhl@163.comPurpose: Airway remodeling is an important feature of chronic asthma, and yet there are few effective therapeutic strategies. Progranulin (PGRN) has been shown to have lung protective functions, but the role of PGRN in asthmatic airway remodeling is unclear. We aim to explore the protective potential of PGRN on house dust mite (HDM)-induced airway remodeling and the underlying mechanisms.Methods: In this study, a murine model of chronic asthma was established by HDM sensitization and challenge. Recombinant PGRN was intranasally administrated to mice during the phase of HDM challenge. TGF-β 1-treated human airway epithelial BEAS-2B cells were utilized to explore the effect of PGRN on airway epithelia exposed to profibrotic conditions and molecular mechanisms.Results: We found that PGRN treatment attenuated HDM-induced airway remodeling, as evidenced by the suppression of collagen accumulation, mucus overproduction and airway smooth muscle synthesis in HDM-challenged asthmatic mice lungs. Meanwhile, PGRN also reversed the increased levels of autophagy markers and autophagosomes in airway epithelia under mimic asthmatic conditions, thereby controlling the fibrotic process in vivo and in vitro. Specifically, overexpressed HMGB1 and the subsequent RAGE/MAPKs signaling activation due to HDM exposure were abrogated in PGRN-treated asthmatic mice. Furthermore, knockdown of HMGB1 expression significantly restrained the fibrosis formation in TGF-β 1-induced airway epithelia accompanied by the downregulation of autophagic activity. However, enhancement of extracellular HMGB1 levels blunted the inhibition of autophagic flux by PGRN in airway epithelia, thereby resulting in the augmentation of collagen synthesis and fibrosis.Conclusion: Taken together, our data revealed that PGRN protected against asthmatic airway remodeling by negatively regulating autophagy via HMGB1 suppression, which might provide new insights into the therapeutic options for HDM-induced chronic asthma.Keywords: house dust mite-induced asthma, airway remodeling, progranulin, autophagy, HMGB1Liu MShan MZhang YGuo ZDove Medical Pressarticlehouse dust mite-induced asthmaairway remodelingprogranulinautophagyhmgb1PathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 3891-3904 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	house dust mite-induced asthma airway remodeling progranulin autophagy hmgb1 Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	house dust mite-induced asthma airway remodeling progranulin autophagy hmgb1 Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Liu M Shan M Zhang Y Guo Z Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma
description	Meixuan Liu,1,2 Mengtian Shan,1 Yunxuan Zhang,3 Zhongliang Guo1,2 1Department of Respiratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200123, People’s Republic of China; 2Department of Respiratory Medicine, Shanghai East Clinical Medical College, Nanjing Medical University, Shanghai, 200123, People’s Republic of China; 3Department of Pharmacy, Huadong Hospital, Fudan University, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Zhongliang Guo Tel +86 18901681968Email drguozhl@163.comPurpose: Airway remodeling is an important feature of chronic asthma, and yet there are few effective therapeutic strategies. Progranulin (PGRN) has been shown to have lung protective functions, but the role of PGRN in asthmatic airway remodeling is unclear. We aim to explore the protective potential of PGRN on house dust mite (HDM)-induced airway remodeling and the underlying mechanisms.Methods: In this study, a murine model of chronic asthma was established by HDM sensitization and challenge. Recombinant PGRN was intranasally administrated to mice during the phase of HDM challenge. TGF-β 1-treated human airway epithelial BEAS-2B cells were utilized to explore the effect of PGRN on airway epithelia exposed to profibrotic conditions and molecular mechanisms.Results: We found that PGRN treatment attenuated HDM-induced airway remodeling, as evidenced by the suppression of collagen accumulation, mucus overproduction and airway smooth muscle synthesis in HDM-challenged asthmatic mice lungs. Meanwhile, PGRN also reversed the increased levels of autophagy markers and autophagosomes in airway epithelia under mimic asthmatic conditions, thereby controlling the fibrotic process in vivo and in vitro. Specifically, overexpressed HMGB1 and the subsequent RAGE/MAPKs signaling activation due to HDM exposure were abrogated in PGRN-treated asthmatic mice. Furthermore, knockdown of HMGB1 expression significantly restrained the fibrosis formation in TGF-β 1-induced airway epithelia accompanied by the downregulation of autophagic activity. However, enhancement of extracellular HMGB1 levels blunted the inhibition of autophagic flux by PGRN in airway epithelia, thereby resulting in the augmentation of collagen synthesis and fibrosis.Conclusion: Taken together, our data revealed that PGRN protected against asthmatic airway remodeling by negatively regulating autophagy via HMGB1 suppression, which might provide new insights into the therapeutic options for HDM-induced chronic asthma.Keywords: house dust mite-induced asthma, airway remodeling, progranulin, autophagy, HMGB1
format	article
author	Liu M Shan M Zhang Y Guo Z
author_facet	Liu M Shan M Zhang Y Guo Z
author_sort	Liu M
title	Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma
title_short	Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma
title_full	Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma
title_fullStr	Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma
title_full_unstemmed	Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma
title_sort	progranulin protects against airway remodeling through the modulation of autophagy via hmgb1 suppression in house dust mite-induced chronic asthma
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/e0d00c64a40f4ed6a2adaeb5b210bb9a
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Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma

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