NBS1 is required for macrophage homeostasis and functional activity in mice.
Nijmegen breakage syndrome 1 (NBS1) is a component of the MRE11 complex, which is a sensor of DNA double-strand breaks and plays a crucial role in the DNA damage response. 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, Nbs1(∆B/∆B), 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, Nbs1(∆B/∆B) macrophages exhibited increased expression of proinflammatory cytokines. In the in vivo 2,4-dinitrofluorobenzene model of inflammation, Nbs1(∆B/∆B) animals showed increased weight and ear thickness. By using the sterile inflammation by zymosan injection, we found that macrophage proliferation was drastically decreased in the peritoneal cavity of Nbs1(∆B/∆B) 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 patients with NBS and related disorders.
Biology of Macrophage, Department of Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain; and.
Selma
S
Pereira-Lopes
Biology of Macrophage, Department of Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain; and.
Juan
J
Tur
Biology of Macrophage, Department of Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain; and.
Juan A
JA
Calatayud-Subias
Biology of Macrophage, Department of Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain; and.
Jorge
J
Lloberas
Institute for Research in Biomedicine, Barcelona, Barcelona, Spain.
Travis H
TH
Stracker
Biology of Macrophage, Department of Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain; and.
Antonio
A
Celada
D000375:Aging / Q000276:immunology* / Q000473:pathology; D000818:Animals; D018797:Cell Cycle Proteins / Q000276:immunology*; D045643:DNA Repair Enzymes / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D000076228:MRE11 Homologue Protein; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000276:immunology*; D015054:Zymosan / Q000633:toxicity
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D007371:Interferon-gamma; D015054:Zymosan; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes