title: 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.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602,USA.
authors.forename: Renfeng
authors.initials: R
authors.lastname: Guo
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Long
authors.initials: L
authors.lastname: Xu
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Li
authors.initials: L
authors.lastname: Du
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Ruoxi
authors.initials: R
authors.lastname: Li
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Fengjun
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Qianjun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address: zhumx@nic.bmi.ac.cn.
authors.forename: Maoxiang
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address: aaronpancn@126.com.
authors.forename: Xiujie
authors.initials: X
authors.lastname: Pan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D016130:Immunophenotyping; D007371:Interferon-gamma; D018664:Interleukin-12; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors; D015847:Interleukin-4; D015848:Interleukin-5; D008212:Lymphocyte Depletion; D051379:Mice; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*; D014965:X-Rays / Q000009:adverse effects
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D015848:Interleukin-5; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: Fibrocyte; Irradiation-induced pulmonary fibrosis; Regulatory T cells; Th1/Th2 cytokines; Th17 cells