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

L-X Xia,Y Jin,W Li,Z-H Chen,C Zhang,F Lan,H-Q Huang,H-H Shen,H-B Zhou,L-Q Che,S-M Ying,B-P Tian,Y-H Ke,W Hua,Z-W Qiu,Y-F Wu,J J Lee

doi:10.1038/cddis.2016.74

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 (LysMcreshp2flox/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.

Highlights

Eosinophils appear to be the key effector cells in asthma, and there is a positive correlation between increased numbers and activation of eosinophils and the severity of asthma.[1,2,3]
By using the SHP2 inhibitor PHPS-1 and deleting shp[2] in myeloid cells, we found that inactivation or loss of SHP2 in these cells decreased the level of eosinophil recruitment to the airway, resulting in alleviation of lung inflammation and reduction of airway hyper-responsiveness (AHR), which were most likely through a direct inhibition of eosinophil differentiation
To begin to test the function of SHP2 in eosinophil differentiation, we first analyzed the effect of phenylhydrazonopyrazolone sulfonate, PHPS-1,25 as a cell-permeable compound, which is highly specific for SHP2 over the closely related tyrosine phosphatases Shp[1] and PTP1B, on the outgrowth of eosinophils from purified bone-marrow cells

Summary

Introduction

Eosinophils appear to be the key effector cells in asthma, and there is a positive correlation between increased numbers and activation of eosinophils and the severity of asthma.[1,2,3]. The protein tyrosine phosphatase SHP2 is a ubiquitously expressed intracellular enzyme that contains two Src homology 2 domains and one catalytic protein tyrosine phosphatase domain.[10,11,12] SHP2 integrates multiple signaling events and mediates a variety of physiological functions.[13,14,15] Studies have shown that SHP2 participates in multiple signaling events by mediating T-cell development and function, and stimulating CEBPA gene expression to regulate cytokinedependent granulopoiesis.[16,17] Normal SHP2 function is critical for the initial step of embryonic stem (ES) cell differentiation to mesoderm and to hemangioblasts It acts within the LIF-gp130-Stat[3] pathway to keep a proper balance of ES cell differentiation, pluripotency and apoptosis, thereby maintaining a functional hematopoietic stem cell/progenitor pool.[13,18,19,20] Pazdrak et al.[21,22,23] demonstrated that the physical association of SHP2 with the phosphorylated α common chain of the IL-5 receptor (IL-5αcR) and Grb[2], and its early activation, are required for coupling of the receptor to the Ras-Raf-MAP/Erk[2] pathway and for the prevention of eosinophil death by IL-5, and shp[2] may act as both a positive

Methods

Results

Conclusion