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Published on: July 12, 2024
PM2.5 induces lung injury via mtDNA-cGAS-STING-mediated macrophage M1 polarization
Bingbing Yan1,2, Bomiao Qing2, Manling Jiang2
1Clinical Medicine Department, North Sichuan Medical College, Nanchong, China.
Background:
Exposure to fine particulate matter (PM2.5) is a well-established risk factor for lung inflammation and injury. Macrophages are key innate immune cells in the lung and play critical roles in maintaining pulmonary immune homeostasis and orchestrating inflammatory responses following environmental insults. However, the precise mechanisms by which PM2.5 modulates macrophage function and contributes to lung injury remain incompletely understood. This study aimed to investigate the role of macrophage phenotypic polarization in PM2.5-induced lung injury and the underlying molecular mechanisms.
Methods:
A subacute exposure (21-day) PM2.5 mouse model and bone marrow-derived macrophages (BMDMs) were used in vivo and in vitro to evaluate the effects of PM2.5 on pulmonary inflammation, macrophage polarization, mitochondrial injury, and cGAS-STING signaling activation. Pharmacological inhibition of cGAS was performed using RU.521 to assess the functional role of the cGAS-STING pathway in PM2.5-induced macrophage activation and lung injury. Statistical analyses were conducted to compare differences between experimental groups.
Results:
PM2.5 exposure triggered pulmonary inflammation and tissue injury, accompanied by increased pulmonary macrophage accumulation and polarization toward the pro-inflammatory M1 phenotype. Mechanistically, PM2.5 induced mitochondrial damage in macrophages, leading to mtDNA release and subsequent activation of cGAS-STING signaling. Pharmacological inhibition of cGAS with RU.521 attenuated STING pathway activation, macrophage M1 polarization, and PM2.5-induced pulmonary inflammation and lung injury in mice.
Conclusions:
Our study indicates that PM2.5 promotes lung injury by driving macrophage M1 polarization through an mtDNA-cGAS-STING axis, highlighting cGAS-STING signaling as a potential therapeutic target for PM2.5-related lung injury.
Insights
Fine particulate matter (PM2.5) causes lung injury by promoting M1 macrophage polarization via mitochondrial DNA release and cGAS-STING pathway activation. Inhibiting this pathway may protect against PM2.5-induced lung damage.
Area of Science:
- Environmental Health
- Immunology
- Toxicology
Background:
- Fine particulate matter (PM2.5) exposure is a known risk factor for lung inflammation and injury.
- Macrophages are crucial for lung immune responses but mechanisms of PM2.5-induced dysfunction are unclear.
Purpose of the Study:
- Investigate macrophage polarization in PM2.5-induced lung injury.
- Elucidate the molecular mechanisms, including mitochondrial injury and cGAS-STING signaling.
Main Methods:
- Utilized a 21-day PM2.5 mouse model and bone marrow-derived macrophages (BMDMs) for in vivo and in vitro studies.
- Assessed pulmonary inflammation, macrophage polarization, mitochondrial damage, and cGAS-STING activation.
- Employed pharmacological inhibition of cGAS (RU.521) to evaluate pathway involvement.
Main Results:
- PM2.5 exposure led to pulmonary inflammation, tissue injury, and M1 macrophage polarization.
- PM2.5 induced mitochondrial damage, mtDNA release, and subsequent cGAS-STING pathway activation.
- RU.521 treatment attenuated STING activation, M1 polarization, and lung injury in mice.
Conclusions:
- PM2.5 drives lung injury via M1 macrophage polarization through an mtDNA-cGAS-STING signaling axis.
- The cGAS-STING pathway is a key mediator of PM2.5-induced lung inflammation and injury.
- Targeting cGAS-STING signaling presents a potential therapeutic strategy for PM2.5-related lung diseases.
