title: Eosinophil differentiation in the bone marrow is promoted by protein tyrosine phosphatase SHP2.
abstract: SHP2 participates in multiple signaling events by mediating T-cell development and function, and regulates cytokine-dependent granulopoiesis. To explore whether and how SHP2 can regulate bone-marrow eosinophil differentiation, we investigate the contribution of SHP2 in the bone-marrow eosinophil development in allergic mice. Blockade of SHP2 function by SHP2 inhibitor PHPS-1 or conditional shp2 knockdown by adenovirus-inhibited bone-marrow-derived eosinophil differentiation in vitro, with no detectable effects on the apoptosis of eosinophils. Furthermore, SHP2 induced eosinophil differentiation via regulation of the extracellular signal-regulated kinase pathway. Myeloid shp2 conditional knockout mice (LysM(cre)shp2(flox/flox)) failed to induce eosinophilia as well as airway hyper-responsiveness. The SHP2 inhibitor PHPS-1 also alleviated eosinophilic airway inflammation and airway hyper-responsiveness, accompanied by significantly reduced levels of systemic eosinophils and eosinophil lineage-committed progenitors in allergic mice. We demonstrate that inhibition of eosinophil development is SHP2-dependent and SHP2 is sufficient to promote eosinophil formation in vivo. Our data reveal SHP2 as a critical regulator of eosinophil differentiation, and inhibition of SHP2 specifically in myeloid cells alleviates allergic airway inflammation.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: L-x
authors.initials: LX
authors.lastname: Xia
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: W
authors.initials: W
authors.lastname: Hua
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: B-p
authors.initials: BP
authors.lastname: Tian
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: Z-w
authors.initials: ZW
authors.lastname: Qiu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: L-q
authors.initials: LQ
authors.lastname: Che
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: H-b
authors.initials: HB
authors.lastname: Zhou
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: Y-f
authors.initials: YF
authors.lastname: Wu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: H-q
authors.initials: HQ
authors.lastname: Huang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: F
authors.initials: F
authors.lastname: Lan
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Y-h
authors.initials: YH
authors.lastname: Ke
authors.affiliation: Division of Pulmonary Medicine and Hematology and Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale 85259, Arizona.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: S-m
authors.initials: SM
authors.lastname: Ying
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
authors.forename: Z-h
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.|The State Key Laboratory of Respiratory Diseases, Guangzhou, Guangdong 510120, China.
authors.forename: H-h
authors.initials: HH
authors.lastname: Shen
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology / Q000378:metabolism / Q000662:veterinary; D001557:Benzenesulfonates / Q000633:toxicity; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006835:Hydrazones / Q000633:toxicity; D015848:Interleukin-5 / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001557:Benzenesulfonates; D016207:Cytokines; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D006835:Hydrazones; D015848:Interleukin-5; C499047:Mbp protein, mouse; D008565:Membrane Proteins; D004676:Myelin Basic Protein; D011994:Recombinant Proteins; C084881:flt3 ligand protein; C529675:phenylhydrazonopyrazolone sulfonate 1; D010047:Ovalbumin; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse