Eosinophil differentiation in the bone marrow is promoted by protein tyrosine phosphatase SHP2

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>in vitro</jats:italic>, 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 (<jats:italic>LysM</jats:italic><jats:sup><jats:italic>cre</jats:italic></jats:sup><jats:italic>shp2</jats:italic><jats:sup><jats:italic>flox/flox</jats:italic></jats:sup>) 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 <jats:italic>in vivo</jats:italic>. Our data reveal SHP2 as a critical regulator of eosinophil differentiation, and inhibition of SHP2 specifically in myeloid cells alleviates allergic airway inflammation.</jats:p>