Genetic functions of the NAIP family of inflammasome receptors for bacterial ligands in mice.
Biochemical studies suggest that the NAIP family of NLR proteins are cytosolic innate receptors that directly recognize bacterial ligands and trigger NLRC4 inflammasome activation. In this study, we generated Naip5(-/-), Naip1(-/-), and Naip2(-/-) mice and showed that bone marrow macrophages derived from these knockout mice are specifically deficient in detecting bacterial flagellin, the type III secretion system needle, and the rod protein, respectively. Naip1(-/-), Naip2(-/-), and Naip5(-/-) mice also resist lethal inflammasome activation by the corresponding ligand. Furthermore, infections performed in the Naip-deficient macrophages have helped to define the major signal in Legionella pneumophila, Salmonella Typhimurium and Shigella flexneri that is detected by the NAIP/NLRC4 inflammasome. Using an engineered S. Typhimurium infection model, we demonstrate the critical role of NAIPs in clearing bacterial infection and protecting mice from bacterial virulence-induced lethality. These results provide definitive genetic evidence for the important physiological function of NAIPs in antibacterial defense and inflammatory damage-induced lethality in mice.
National Institute of Biological Sciences, 102206 Beijing, China.
Yue
Y
Zhao
National Institute of Biological Sciences, 102206 Beijing, China.
Jianjin
J
Shi
National Institute of Biological Sciences, 102206 Beijing, China.
Xuyan
X
Shi
National Institute of Biological Sciences, 102206 Beijing, China.
Yupeng
Y
Wang
National Institute of Biological Sciences, 102206 Beijing, China.
Fengchao
F
Wang
National Institute of Biological Sciences, 102206 Beijing, China Collaborative Innovation Center for Cancer Medicine, National Institute of Biological Sciences, 102206 Beijing, China shaofeng@nibs.ac.cn.
Feng
F
Shao
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D006090:Gram-Negative Bacteria / Q000276:immunology / Q000472:pathogenicity; D016905:Gram-Negative Bacterial Infections / Q000276:immunology*; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics / Q000276:immunology*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*
D058847:Inflammasomes; C496801:Naip1 protein, mouse; C496802:Naip2 protein, mouse; C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D037521:Virulence Factors