HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury

Min Zhou,1,* Yadi Zhang,2,* Rui Tang,1 Haiyan Liu,1 Min Du,1 Zhi Gao,1 Zongshu Ji,1 Haoshu Fang3 1Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic o...

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Autores principales:	Zhou M, Zhang Y, Tang R, Liu H, Du M, Gao Z, Ji Z, Fang H
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	hmgb1 tlr4 treg acute lung injury Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/90ae7db2630a408ba9897cbcf3f529ae
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spelling	oai:doaj.org-article:90ae7db2630a408ba9897cbcf3f529ae2021-12-02T15:54:01ZHMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury1178-7031https://doaj.org/article/90ae7db2630a408ba9897cbcf3f529ae2021-04-01T00:00:00Zhttps://www.dovepress.com/hmgb1tlr4-signaling-affects-regulatory-t-cells-in-acute-lung-injury-peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Min Zhou,1,* Yadi Zhang,2,* Rui Tang,1 Haiyan Liu,1 Min Du,1 Zhi Gao,1 Zongshu Ji,1 Haoshu Fang3 1Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2Department of Respiratory Medicine, The Second People’s Hospital of Hefei and Hefei Hospital Affiliated with Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China; 3Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haoshu FangDepartment of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, People’s Republic of ChinaTel +86 551-65161129Email fang.haoshu@hotmail.comBackground: High-mobility group box-1 protein (HMGB1) serves as the prototypic damage-associated molecular pattern molecule, and TLR4 is considered a receptor for HMGB1. Regulatory T cells (Tregs) play a crucial role in infectious diseases. The role of HMGB1 in the modulation of Tregs is of great interest.Methods: Serum HMGB1 and Treg proportions were detected in 58 patients with acute lung injury (ALI) and 36 healthy volunteers. The correlations of these parameters with disease severity were analyzed. The WT and TLR4-/- mice were administered HMGB1 by intratracheal injection. After 48 h, the mice were sacrificed. The morphological changes and wet/dry ratio of the lung were measured. Spleen CD4+CD25+ Tregs were sorted from spleen cells, the expression of FOXP3 and CTLA-4, and releasing of cytokines was detected. CD4+CD25+ Tregs were cocultured with effector T cells, the inhibitory effect, and release of cytokines was detected.Results: Significantly increased plasma levels of HMGB1 and reduced CD4+CD25+CD127low Tregs were detected in ALI patients. In the mouse model, lung injury was significantly increased after HMGB1 instillation in the WT and TLR4-/- groups compared with control group. The lung wet/dry ratio and the TNF-α and IL-1β contents in BALF were significantly increased, and the severity of WT mice was higher than that of TLR4-/- mice. The expression of FOXP3 and CTLA-4 in TLR4-/- mice was significantly increased compared with that in WT mice and was associated with a similar trend of IL-10 and TGF-β levels (p< 0.05). In coculture with effector T cells, Tregs isolated from TLR4-/- mice exhibited decreased IL-2 and IFN-γ and increased IL-4 levels compared with Tregs from WT mice. Increased polarization of TLR4-/- CD4+CD25+ Treg cells to Th2 cells was observed.Conclusion: In HMGB1-induced lung injury, HMGB1 affects the expression of FOXP3 and CTLA-4 through TLR4, thus reducing the immunosuppressive function of Treg cells.Keywords: HMGB1, TLR4, Treg, acute lung injuryZhou MZhang YTang RLiu HDu MGao ZJi ZFang HDove Medical Pressarticlehmgb1tlr4tregacute lung injuryPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 1551-1561 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	hmgb1 tlr4 treg acute lung injury Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	hmgb1 tlr4 treg acute lung injury Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Zhou M Zhang Y Tang R Liu H Du M Gao Z Ji Z Fang H HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury
description	Min Zhou,1,* Yadi Zhang,2,* Rui Tang,1 Haiyan Liu,1 Min Du,1 Zhi Gao,1 Zongshu Ji,1 Haoshu Fang3 1Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2Department of Respiratory Medicine, The Second People’s Hospital of Hefei and Hefei Hospital Affiliated with Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China; 3Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haoshu FangDepartment of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, People’s Republic of ChinaTel +86 551-65161129Email fang.haoshu@hotmail.comBackground: High-mobility group box-1 protein (HMGB1) serves as the prototypic damage-associated molecular pattern molecule, and TLR4 is considered a receptor for HMGB1. Regulatory T cells (Tregs) play a crucial role in infectious diseases. The role of HMGB1 in the modulation of Tregs is of great interest.Methods: Serum HMGB1 and Treg proportions were detected in 58 patients with acute lung injury (ALI) and 36 healthy volunteers. The correlations of these parameters with disease severity were analyzed. The WT and TLR4-/- mice were administered HMGB1 by intratracheal injection. After 48 h, the mice were sacrificed. The morphological changes and wet/dry ratio of the lung were measured. Spleen CD4+CD25+ Tregs were sorted from spleen cells, the expression of FOXP3 and CTLA-4, and releasing of cytokines was detected. CD4+CD25+ Tregs were cocultured with effector T cells, the inhibitory effect, and release of cytokines was detected.Results: Significantly increased plasma levels of HMGB1 and reduced CD4+CD25+CD127low Tregs were detected in ALI patients. In the mouse model, lung injury was significantly increased after HMGB1 instillation in the WT and TLR4-/- groups compared with control group. The lung wet/dry ratio and the TNF-α and IL-1β contents in BALF were significantly increased, and the severity of WT mice was higher than that of TLR4-/- mice. The expression of FOXP3 and CTLA-4 in TLR4-/- mice was significantly increased compared with that in WT mice and was associated with a similar trend of IL-10 and TGF-β levels (p< 0.05). In coculture with effector T cells, Tregs isolated from TLR4-/- mice exhibited decreased IL-2 and IFN-γ and increased IL-4 levels compared with Tregs from WT mice. Increased polarization of TLR4-/- CD4+CD25+ Treg cells to Th2 cells was observed.Conclusion: In HMGB1-induced lung injury, HMGB1 affects the expression of FOXP3 and CTLA-4 through TLR4, thus reducing the immunosuppressive function of Treg cells.Keywords: HMGB1, TLR4, Treg, acute lung injury
format	article
author	Zhou M Zhang Y Tang R Liu H Du M Gao Z Ji Z Fang H
author_facet	Zhou M Zhang Y Tang R Liu H Du M Gao Z Ji Z Fang H
author_sort	Zhou M
title	HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury
title_short	HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury
title_full	HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury
title_fullStr	HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury
title_full_unstemmed	HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury
title_sort	hmgb1/tlr4 signaling affects regulatory t cells in acute lung injury
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/90ae7db2630a408ba9897cbcf3f529ae
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HMGB1/TLR4 Signaling Affects Regulatory T Cells in Acute Lung Injury

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