Dexamethasone alleviates pulmonary sarcoidosis by regulating the TGF-β/Smad3 signaling to promote Th17/Treg cell rebalance

Yu Zhang; Xuan Jiang; Qing Wang; Jiayi Wu; Juan Zhou

doi:10.1016/j.cellimm.2023.104781

Dexamethasone alleviates pulmonary sarcoidosis by regulating the TGF-β/Smad3 signaling to promote Th17/Treg cell rebalance

Cell Immunol. 2024 Jan-Feb:395-396:104781. doi: 10.1016/j.cellimm.2023.104781. Epub 2023 Nov 2.

Authors

Yu Zhang¹, Xuan Jiang², Qing Wang³, Jiayi Wu³, Juan Zhou⁴

Affiliations

¹ Department of Respiratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214000, China; Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, China.
² Department of Respiratory Medicine, Wuxi Second People's Hospital, Wuxi, Jiangsu 214000, China.
³ Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, China.
⁴ Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Nantong University, No. 20, Xisi Road, Nantong, Jiangsu 226000, China. Electronic address: zhoujuan_1974@outlook.com.

PMID: 38159414
DOI: 10.1016/j.cellimm.2023.104781

Abstract

Pulmonary sarcoidosis is an immune-mediated disorder closely related to Th17/Treg cell imbalance. Dexamethasone has been shown to regulate inflammation and immune responses in sarcoidosis patients. However, the underlying mechanisms of dexamethasone regulating Th17/Treg balance in sarcoidosis remain elusive. Herein, we elucidated the function role of TGF-β/Smad3 signaling in pulmonary sarcoidosis development and explored the underlying mechanism of dexamethasone in treating pulmonary sarcoidosis. We found that the TGF-β/Smad3 pathway was inactivated in pulmonary sarcoidosis patients. Propionibacterium acnes (PA) induced mouse model was generated to investigate the function of TGF-β/Smad3 signaling in vivo. Data indicated that IL17A inhibition with neutralizing antibody and activation of TGF-β/Smad3 signaling with SRI-011381 alleviated granuloma formation in the sarcoidosis mouse model. Moreover, we revealed that the Th17/Treg cell ratio was increased with PA treatment in mouse bronchoalveolar lavage fluid (BALF) and peripheral blood. The concentration of cytokines produced by Th17 cells (IL-17A, IL-23) was up-regulated in the BALF of PA-treated mice, while those produced by Tregs (IL-10, TGF-β1) presented significant reduction. The treatment of IL-17A neutralizing antibody or SRI-011381 was demonstrated to rescue the PA-induced changes in the concentration of IL-17A, IL-23, IL-10, and TGF-β1. Additionally, we demonstrated that dexamethasone treatment activated the TGF-β/Smad3 signaling in the lung tissues of pulmonary sarcoidosis mice. Dexamethasone was also revealed to promote the rebalancing of the Th17/Treg ratio and attenuated the granuloma formation in pulmonary sarcoidosis. In conclusion, dexamethasone activates the TGF-β/Smad3 signaling and induces Th17/Treg rebalance, alleviating pulmonary sarcoidosis, which suggests the potential of dexamethasone in treating pulmonary sarcoidosis.

Keywords: Dexamethasone; Immune cells; Pulmonary sarcoidosis; TGF-β/Smad3 signaling; Th17/Treg balance.

MeSH terms

Animals
Antibodies, Neutralizing / pharmacology
Dexamethasone* / pharmacology
Dexamethasone* / therapeutic use
Granuloma / prevention & control
Humans
Interleukin-10 / metabolism
Interleukin-17
Interleukin-23 / metabolism
Mice
Sarcoidosis, Pulmonary* / drug therapy
T-Lymphocytes, Regulatory
Th17 Cells
Transforming Growth Factor beta / metabolism
Transforming Growth Factor beta1

Substances

Antibodies, Neutralizing
Dexamethasone
Interleukin-10
Interleukin-17
Interleukin-23
Transforming Growth Factor beta
Transforming Growth Factor beta1