NBS1 is required for macrophage homeostasis and functional activity in mice

Abstract

Nijmegen breakage syndrome 1 (NBS1) is a component of the MRE11 complex, which is a sensor ofDNAdouble-strand breaks and plays a crucial role in theDNAdamageresponse. Because activated macrophages produce large amounts of reactive oxygen species (ROS) that can cause DNA lesions, we examined the role of NBS1 in macrophage functional activity. Proliferative and proinflammatory (interferon gamma [IFN-γ] and lipopolysaccharide [LPS]) stimuli led to increased NBS1 levels in macrophages. In mice expressing a hypomorphic allele of Nbs1, Nbs1ΔB/ΔB, macrophage activation-induced ROS caused increased levels of DNA damage that were associated with defects in proliferation, delayed differentiation, and increased senescence. Furthermore, upon stimulation, Nbs1ΔB/ΔB macrophages exhibited increased expression of proinflammatory cytokines. In the in vivo 2,4-dinitrofluorobenezene model of inflammation, Nbs1ΔB/ΔB animals showed increased weight and ear thickness.By using the sterile inflammation by zymosan injection,we found thatmacrophage proliferationwas drastically decreased in the peritoneal cavity ofNbs1ΔB/ΔB mice. Our findings show that NBS1 is crucial for macrophage function during normal aging. These results have implications for understanding the immune defects observed in patientswithNBS and related disorders.