Deficiency of Src homology 2-containing phosphatase 1 results in abnormalities in murine neutrophil function: Studies in motheaten mice

Neutrophils, an essential component of the innate immune system, are regula ted in part by signaling pathways involving protein tyrosine phosphorylatio n. While protein tyrosine kinase functions in regulating neutrophil behavio r have been extensively investigated, little is known about the role for sp ecific protein tyrosine phosphatases (PTP) in modulating neutrophil signali ng cascades. A key role for Src homology 2 domain-containing phosphatase 1 (SHP-1), a PTP, in neutrophil physiology is, however, implied by the overex pansion and inappropriate activation of granulocyte populations in SHP-1-de ficient motheaten (me/me) and motheaten viable (me(v)/me(v)) mice. To direc tly investigate the importance of SHP-1 to phagocytic cell function, bone m arrow neutrophils were isolated from both me/me and me(v)/me(v) mice and ex amined with respect to their responses to various stimuli. The results of t hese studies revealed that both quiescent and activated neutrophils from mo theaten mice manifested enhanced tyrosine phosphorylation of cellular prote ins in the 60- to 80-kDa range relative to that detected in wild-type conge nic control neutrophils, Motheaten neutrophils also demonstrated increased oxidant production, surface expression of CD18, and adhesion to protein-coa ted plastic. Chemotaxis, however, was severely diminished in the SHP-defici ent neutrophils relative to control neutrophils, which was possibly attribu table to a combination of defective deadhesion and altered actin assembly. Taken together, these results indicate a significant role for SHP-1 in modu lating the tyrosine phosphorylation-dependent signaling pathways that regul ate neutrophil microbicidal functions.