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

Date Published: April 14, 2018

Publisher: Impact Journals

Author(s): Man Luo, Zhengqiang Bao, Feng Xu, Xiaohui Wang, Fei Li, Wen Li, Zhihua Chen, Songmin Ying, Huahao Shen.

http://doi.org/10.18632/aging.101412

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.

Partial Text

Airborne particulate matter (PM) pollution is a leading contributor to global disease burden [1]. Substantial epidemiological and clinical studies have documented that exposure to ambient air pollution is closely correlated with acute exacerbation of asthma and chronic obstructive pulmonary disease, respiratory tract infection and lung cancer incidence [2-5]. Therefore, it is of vital importance to determine the mechanisms responsible for pulmonary injury by PM and to develop potential therapy.

In this present study, we found that DDR signaling play an important role in PM-induced inflammatory responses in macrophages. We have shown that PM can trigger direct DNA damage and subsequent DDR signaling in macrophages both in vitro and in vivo and that genetic ablation or chemical inhibition of DDR augments PM-induced cytokine production in BMDMs. Meanwhile, myeloid-specific deletion of the DDR–related gene RAD50 exacerbates airway inflammation in response to PM exposure in vivo.

In summary, this study demonstrates that PM exposure induces DNA damage and subsequently initiates DNA damage response in macrophages. Disruption of MRN complex causes elevated inflammatory response through accumulated unrepaired DNA damage.

 

Source:

http://doi.org/10.18632/aging.101412

 

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