DNA polymerase μ protects macrophages from DNA damage produced during pro-inflammatory activation

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Pro-inflammatory stimuli activate macrophages, leading to reactive oxygen species (ROS) production.
• ROS cause DNA double-strand breaks (DSBs), which can impair macrophage function.
• DNA polymerase μ (Polμ) is a key enzyme in the non-homologous end-joining (NHEJ) DNA repair pathway.

Purpose of the Study:

• To investigate the role of Polμ in macrophage functional activity during inflammation.
• To determine if Polμ is necessary for macrophage survival and proliferation under pro-inflammatory conditions.
• To assess the impact of Polμ deficiency on tissue repair and inflammatory responses in vivo.

Main Methods:

• Macrophages were stimulated with pro-inflammatory agents.
• Polμ expression levels were analyzed in response to stimuli.
• Polμ-deficient macrophages were compared to wild-type macrophages regarding proliferation, apoptosis, and DSB repair.
• Macrophage-dependent muscular regeneration, inflammation, and infection models were used in mice.
• Macrophage survival and inflammatory response at inflammatory foci were evaluated.

Main Results:

• Polμ expression in macrophages is induced by pro-inflammatory stimuli and depends on ROS.
• Polμ-deficient macrophages exhibited reduced proliferation and increased apoptosis under pro-inflammatory conditions, indicating deficient DSB repair.
• Polμ deficiency impaired tissue repair in a mouse model of muscular regeneration due to compromised macrophage survival.
• Polμ is required for macrophages to survive at inflammatory foci and mount an effective inflammatory response in models of inflammation and infection.

Conclusions:

• Polμ plays a critical role in macrophage survival and function during inflammatory responses.
• Polμ is essential for repairing ROS-induced DNA damage in macrophages.
• Polμ enables macrophages to effectively manage oxidative stress and maintain their functional integrity during inflammation and infection.