phenylhydrazonopyrazolone-sulfonate-1 and Asthma

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.

Topics: Animals; Asthma; Benzenesulfonates; Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Cytokines; Disease Models, Animal; Eosinophils; Extracellular Signal-Regulated MAP Kinases; GATA1 Transcription Factor; Hydrazones; Interleukin-5; Lung; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Ovalbumin; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Recombinant Proteins; Signal Transduction