Treg depletion attenuates irradiation-induced pulmonary fibrosis by reducing fibrocyte accumulation, inducing Th17 response, and shifting IFN-γ, IL-12/IL-4, IL-5 balance.

Abstract

Irradiation-induced pulmonary fibrosis results from thoracic radiotherapy and severely limits radiotherapy approaches. CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) are involved in experimentally induced murine lung fibrosis. However, the precise contribution of Tregs to irradiation-induced pulmonary fibrosis still remains unclear. We have previously established the mouse model of irradiation-induced pulmonary fibrosis and observed an increased frequency of Tregs during the process. This study aimed to investigate the effects of Treg depletion on irradiation-induced pulmonary fibrosis and on fibrocyte, Th17 cell response and production of multiple cytokines in mice. Treg-depleted mice were generated by intraperitoneal injection with anti-CD25 mAb 2h after 20 Gy (60)CO γ-ray thoracic irradiation and every 7 days thereafter. Pulmonary fibrosis was semi-quantitatively assessed using Masson's trichrome staining. The proportions of Tregs, fibrocyte and Th17 cells were detected by flow cytometry. Th1/Th2 cytokines were assessed by Luminex assays. We found that Treg depletion decelerated the process of irradiation-induced pulmonary fibrosis and hindered fibrocyte recruitment to the lung. In response to Treg depletion, the number of CD4(+) T lymphocytes and Th17 cells increased. Moreover, Th1/Th2 cytokine balance was disturbed into Th1 dominance upon Treg depletion. Our study demonstrates that Tregs are involved in irradiation-induced pulmonary fibrosis by promoting fibrocyte accumulation, attenuating Th17 response and regulating Th1/Th2 cytokine balance in the lung tissues, which suggests that Tregs may be therapeutically manipulated to decelerate the progression of irradiation-induced pulmonary fibrosis.

• Authors: Shanshan Xiong, Renfeng Guo, Zhihua Yang, Long Xu, Li Du, Ruoxi Li, Fengjun Xiao, Qianjun Wang, Maoxiang Zhu, Xiujie Pan
• Journal: Immunobiology (Immunobiology) Vol. 220 Issue 11 Pg. 1284-91 (Nov 2015) ISSN: 1878-3279 [Electronic] Netherlands
• PMID: 26224246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier GmbH.

Chemical References

• Antibodies, Monoclonal
• Cytokines
• Interleukin-2 Receptor alpha Subunit
• Interleukin-5
• Interleukin-12
• Interleukin-4
• Interferon-gamma

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• CD4 Lymphocyte Count
• Cytokines (metabolism)
• Female
• Immunophenotyping
• Interferon-gamma
• Interleukin-12
• Interleukin-2 Receptor alpha Subunit (antagonists & inhibitors)
• Interleukin-4
• Interleukin-5
• Lymphocyte Depletion
• Mice
• Phenotype
• Pulmonary Fibrosis (etiology, pathology)
• T-Lymphocyte Subsets (immunology, metabolism)
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Th17 Cells (immunology, metabolism)
• X-Rays (adverse effects)