RESUMO
Mast cells play critical roles in allergic responses. Calcium signaling controls the function of these cells, and a role for actin in regulating calcium influx into cells has been suggested. We have previously identified the actin reorganizing protein Drebrin as a target of the immunosuppressant 3,5-bistrifluoromethyl pyrazole, which inhibits calcium influx into cells. In this study, we show that Drebrin(-/-) mice exhibit reduced IgE-mediated histamine release and passive systemic anaphylaxis, and Drebrin(-/-) mast cells also exhibit defects in FcεRI-mediated degranulation. Drebrin(-/-) mast cells exhibit defects in actin cytoskeleton organization and calcium responses downstream of the FcεRI, and agents that relieve actin reorganization rescue mast cell FcεRI-induced degranulation. Our results indicate that Drebrin regulates the actin cytoskeleton and calcium responses in mast cells, thus regulating mast cell function in vivo.
Assuntos
Citoesqueleto de Actina/imunologia , Actinas/imunologia , Anafilaxia/imunologia , Mastócitos/imunologia , Neuropeptídeos/imunologia , Receptores de IgG/imunologia , Citoesqueleto de Actina/química , Citoesqueleto de Actina/patologia , Actinas/genética , Anafilaxia/induzido quimicamente , Anafilaxia/genética , Anafilaxia/patologia , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Degranulação Celular/imunologia , Regulação da Expressão Gênica , Imunoglobulina E/administração & dosagem , Imunoglobulina E/química , Imunossupressores/farmacologia , Mastócitos/patologia , Camundongos , Camundongos Knockout , Neuropeptídeos/genética , Pirazóis/farmacologia , Receptores de IgG/genética , Albumina Sérica/química , Albumina Sérica/imunologiaRESUMO
Eosinophils are critical cellular mediators in allergic asthma and inflammation; however, the signals that regulate their functions are unclear. The transcription factor STAT6 regulates Th2 cytokine responses, acting downstream of IL-4 and IL-13. We showed previously that eosinophil-derived IL-13 plays an important role in the recruitment of T cells to the lung and the subsequent development of allergic asthma. However, whether eosinophils respond to Th2 signals to control allergic airway inflammation is unclear. In this report, we show that STAT6(-/-) eosinophils are unable to induce the development of allergic lung inflammation, including recruitment of CD4(+) T cells, mucus production, and development of airways hyperresponsiveness. This is likely due to the reduced migration of STAT6(-/-) eosinophils to the lung and in response to eotaxin. These data indicate that, like Th cells, eosinophils need to respond to Th2 cytokines via STAT6 during the development of allergic airway inflammation.