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

Area of Science:

• Immunology
• Molecular Biology
• Toxicology

Background:

• Macrophages are key players in particulate matter (PM)-induced airway inflammation.
• DNA damage recognition initiates the inflammatory cascade.

Purpose of the Study:

• To investigate the role of DNA damage response in macrophages following PM exposure.
• To elucidate the function of DNA damage sensors in PM-induced airway inflammation.

Main Methods:

• Bone marrow-derived macrophages were treated with PM in vitro.
• A mouse model was used with intratracheal PM instillation in vivo.
• DNA damage response markers (RPA, 53BP1, γH2AX foci) and cytokine production were assessed.
• Myeloid-specific deletion of RAD50 was employed to study the DNA damage sensor's role.

Main Results:

• PM exposure induced significant DNA damage and a rapid DNA damage response in macrophages, both in vitro and in vivo.
• Genetic or chemical inhibition of DNA damage sensors amplified pro-inflammatory cytokine production (Cxcl1, Cxcl2, Ifn-γ) after PM stimulation.
• Mice lacking RAD50 in myeloid cells exhibited heightened airway inflammation upon PM challenge, indicating a protective function of the DNA damage sensor.

Conclusions:

• PM exposure triggers DNA damage and activates the MRN complex in macrophages.
• Disruption of the MRN complex leads to unrepaired DNA damage, exacerbating the inflammatory response.
• DNA damage sensors play a protective role in mitigating PM-induced airway inflammation.