title: Phosphatase Wip1 negatively regulates neutrophil migration and inflammation.
abstract: Neutrophils are critically involved in host defense and tissue damage. Intrinsic signal mechanisms controlling neutrophil activities are poorly defined. We found that the expression of wild-type p53-induced phosphatase 1 (Wip1) in mouse and human neutrophils was downregulated quickly after neutrophil activation through JNK-microRNA-16 pathway. Importantly, the Wip1 expression level was negatively correlated with inflammatory cytokine productions of neutrophils in sepsis patients. Wip1-deficient mice displayed increased bactericidal activities to Staphylococcus aureus and were hypersensitive to LPS-induced acute lung damage with increased neutrophil infiltration and inflammation. Mechanism studies showed that the enhanced inflammatory activity of neutrophils caused by Wip1 deficiency was mediated by p38 MAPK-STAT1 and NF-κB pathways. The increased migration ability of Wip1KO neutrophils was mediated by the decreased CXCR2 internalization and desensitization, which was directly regulated by p38 MAPK activity. Thus, our findings identify a previously unrecognized function of Wip1 as an intrinsic negative regulator for neutrophil proinflammatory cytokine production and migration through multiple signal pathways.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
authors.forename: Xuelian
authors.initials: X
authors.lastname: Hu
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.forename: Yamei
authors.initials: Y
authors.lastname: Xu
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Shi
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Hongran
authors.initials: H
authors.lastname: Li
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology*; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000502:physiology*; D000071636:Protein Phosphatase 2C; D012333:RNA, Messenger / Q000096:biosynthesis; D011828:Radiation Chimera; D023063:Receptors, Interleukin-8B / Q000502:physiology; D018805:Sepsis / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C