title: Atg7 enhances host defense against infection via downregulation of superoxide but upregulation of nitric oxide.
abstract: Pseudomonas aeruginosa is an opportunistic bacterium that can cause serious infection in immunocompromised individuals. Although autophagy may augment immune responses against P. aeruginosa infection in macrophages, the critical components and their role of autophagy in host defense are largely unknown. In this study, we show that P. aeruginosa infection-induced autophagy activates JAK2/STAT1α and increases NO production. Knocking down Atg7 resulted in increased IFN-γ release, excessive reactive oxygen species, and increased Src homology-2 domain-containing phosphatase 2 activity, which led to lowered phosphorylation of JAK2/STAT1α and subdued expression of NO synthase 2 (NOS2). In addition, we demonstrated the physiological relevance of dysregulated NO under Atg7 deficiency as atg7(-/-) mice were more susceptible to P. aeruginosa infection with increased mortality and severe lung injury than wild-type mice. Furthermore, P. aeruginosa-infected atg7(-/-) mice exhibited increased oxidation but decreased bacterial clearance in the lung and other organs compared with wild-type mice. Mechanistically, atg7 deficiency suppressed NOS2 activity by downmodulating JAK2/STAT1α, leading to decreased NO both in vitro and in vivo. Taken together, these findings revealed that the JAK2/STAT1α/NOS2 dysfunction leads to dysregulated immune responses and worsened disease phenotypes.
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203; and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203; and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Xikun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China min.wu@med.und.edu hcanhua@hotmail.com.
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203; and min.wu@med.und.edu hcanhua@hotmail.com.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D056809:Alveolar Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D054884:Host-Pathogen Interactions / Q000235:genetics* / Q000276:immunology; D007239:Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D007371:Interferon-gamma / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism*
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; D013481:Superoxides; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D053614:Janus Kinase 2; D000071193:Autophagy-Related Protein 7