Research Paper Volume 10, Issue 4 pp 549—560

Unrepaired DNA damage in macrophages causes elevation of particulate matter- induced airway inflammatory response

Man Luo 1, , Zhengqiang Bao 2, 3, , Feng Xu 1, , Xiaohui Wang 3, , Fei Li 1, , Wen Li 1, , Zhihua Chen 1, , Songmin Ying 1, 3, , Huahao Shen 1, 4, ,

  • 1 Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou 310009, China
  • 2 Cancer Centre, The Second Hospital of Shandong University, Jinan 250033, China
  • 3 Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China
  • 4 State Key Lab of Respiratory Disease, Guangzhou 510120, China

received: February 7, 2018 ; accepted: April 9, 2018 ; published: April 14, 2018 ;

https://doi.org/10.18632/aging.101412
How to Cite

Copyright: Luo et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The inflammatory cascade can be initiated with the recognition of damaged DNA. Macrophages play an essential role in particulate matter (PM)-induced airway inflammation. In this study, we aim to explore the PM induced DNA damage response of macrophages and its function in airway inflammation. The DNA damage response and inflammatory response were assessed using bone marrow–derived macrophages following PM treatment and mouse model instilled intratracheally with PM. We found that PM induced significant DNA damage both in vitro and in vivo and simultaneously triggered a rapid DNA damage response, represented by nuclear RPA, 53BP1 and γH2AX foci formation. Genetic ablation or chemical inhibition of the DNA damage response sensor amplified the production of cytokines including Cxcl1, Cxcl2 and Ifn-γ after PM stimulation in bone marrow–derived macrophages. Similar to that seen in vitro, mice with myeloid-specific deletion of RAD50 showed higher levels of airway inflammation in response to the PM challenge, suggesting a protective role of DNA damage sensor during inflammation. These data demonstrate that PM exposure induces DNA damage and activation of DNA damage response sensor MRN complex in macrophages. Disruption of MRN complex lead to persistent, unrepaired DNA damage that causes elevated inflammatory response.

Abbreviations

AMs: alveolar macrophages; BMDMs: bone marrow–derived macrophages; DDR: DNA damage response; PM: particulate matter; WT: wildtype; NS: normal saline.