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

Activation of macrophages with pro-inflammatory stimuli leads to the generation and secretion of large amounts of reactive oxygen species (ROS), which cause DNA double-strand breaks (DSBs). Here, the role of DNA polymerase μ (Polμ), a component of the non-homologous end-joining (NHEJ) DNA repair pathway of DSBs, in macrophage functional activity during inflammation is evaluated. Polμ is expressed in macrophages upon pro-inflammatory stimuli depending on ROS. Under pro-inflammatory stimuli, Polμ-deficient macrophages exhibit reduced proliferation and enhanced apoptosis, a phenotype associated with deficient DSB repair. In a mouse model of macrophage-dependent muscular regeneration, Polμ deficiency impaired tissue repair associated with macrophage survival. In models of inflammation and infection, Polμ is required for macrophages to subsist at inflammatory foci and mount an effective inflammatory response. These findings show that Polμ is crucial for macrophages to block the unwanted effects of ROS during inflammatory responses.