Function Of SHP-1 Deficient Mast Cells In Allergic Inflammation Of Mice Lung

Phosphatase SHP-1 deficient mice display an allergic asthma phenotype that is largely IL-13 and STAT6 dependent. The cell types responsible for the Th2 phenotype have not been identified. We hypothesized that SHP-1 deficiency leads to mast cell dysregulation and increased production and release of mediators and Th2 cytokines, leading to the allergic asthma phenotype. We examined SHP-1 regulation of mast cell differentiation, survival, and functional responses to stimulation using bone marrow derived mast cells from viable motheaten (mev) mice. We assessed pulmonary phenotypical changes in mev mice on mast cell deficient KitW-Sh genetic background. The results show that SHP-1 deficiency leads to increased differentiation and survival, but reduced proliferation, of mast cells. SHP-1 deficient mast cells produce and release increased amounts of mediators and Th2 cytokines IL-4 and IL-13, spontaneously and in response to H2O2, LPS, and FcεRI cross-linking, involving c-Kit-dependent and independent processes. The FcsRI signaling leads to binding of SHP-1 to LAT2 and enhanced LAT2 phosphorylation in mev BMMC. Furthermore, the number of mast cells in the lung tissue of mev mice is increased and mast cell production and release of Th2 cytokines are distinctly increased upon FcεRI stimulation. When backcrossed to the KitW-Sh background mev mice have markedly reduced pulmonary inflammation and Th2 cytokine production. These findings demonstrate that SHP-1 is a critical regulator of mast cell development and function and that SHP-1 deficient mast cells are able to produce increased Th2 cytokines and to initiate allergic inflammatory responses in the lung.