Potential role of senescent macrophages in radiation-induced pulmonary fibrosis

Lulu Su,Feiyue Fan,Yuquan Wang,Bowen Guan,Yinping Dong,Xiaochun Wang,Aimin Meng,Yueying Wang,Jing Wu,Yanhua Lu,Deguan Li

doi:10.1038/s41419-021-03811-8

Abstract

Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation in clinic with poor prognosis and limited therapeutic options. Previous results have shown that senescent cells, such as fibroblast and type II airway epithelial cell, are strongly implicated in pathology of RIPF. However, the role of senescent macrophages in the development RIPF is still unknown. In this study, we report that ionizing radiation (IR) increase cellular senescence with higher expression of senescence-associated β-galactosidase (SA-β-Gal) and senescence-specific genes (p16, p21, Bcl-2, and Bcl-xl) in irradiated bone marrow-derived monocytes/macrophages (BMMs). Besides, there’s a significant increase in the expression of pro-fibrogenic factors (TGF-β1 and Arg-1), senescence-associated secretory phenotype (SASP) proinflammatory factors (Il-1α, Il-6, and Tnf-α), SASP chemokines (Ccl2, Cxcl10, and Ccl17), and SASP matrix metalloproteinases (Mmp2, Mmp9 and Mmp12) in BMMs exposed to 10 Gy IR. In addition, the percentages of SA-β-Gal+ senescent macrophages are significantly increased in the macrophages of murine irradiated lung tissue. Moreover, robustly elevated expression of p16, SASP chemokines (Ccl2, Cxcl10, and Ccl17) and SASP matrix metalloproteinases (Mmp2, Mmp9, and Mmp12) is observed in the macrophages of irradiated lung, which might stimulate a fibrotic phenotype in pulmonary fibroblasts. In summary, irradiation can induce macrophage senescence, and increase the secretion of SASP in senescent macrophages. Our findings provide important evidence that senescent macrophages might be the target for prevention and treatment of RIPF.

Highlights

The incidence of thoracic cancers has remained generally high over the past few decades, including pulmonary cancer, breast cancer, esophageal cancer, and mediastinal tumors[1]
The secretion of IL-1α, CCL2, and CCL17 robustly increased at 4, 8, or 16 weeks after ionizing radiation (IR), whereas there was no change of IL-1β and tumor necrosis factor-α (TNF-α) in the irradiated lung tissues (Fig. 5B). These results suggested that IR promoted the senescence-associated secretory phenotype (SASP) in senescent macrophages, and the secretome of senescent macrophages might robustly stimulate a fibrotic phenotype in the fibroblasts of irradiated lung
It has shown that senescent cells contribute to the development of radiationinduced pulmonary fibrosis (RIPF), such as senescent fibroblast and type II airway epithelial cell[7,8,9,10]

Summary

Introduction

The incidence of thoracic cancers has remained generally high over the past few decades, including pulmonary cancer, breast cancer, esophageal cancer, and mediastinal tumors[1]. Thoracic cancer patients received radiation therapy are at risk of developing radiationinduced pulmonary fibrosis (RIPF), which is a common complication of radiotherapy and a major limiting factor for oncotherapy[2,3,4]. The culmination of prior studies suggest senescent cells may be crucial contributors to initiation and progression of pulmonary fibrosis (PF), including senescent fibroblast[6,7,8] and senescent type II airway epithelial cell[9,10,11].

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Results

Conclusion