RESUMO
Alternatively activated macrophages (M2) have an important function in innate immune responses to parasitic helminths, and emerging evidence also indicates these cells are regulators of systemic metabolism. Here we show a critical role for mTORC2 signalling in the generation of M2 macrophages. Abrogation of mTORC2 signalling in macrophages by selective conditional deletion of the adaptor molecule Rictor inhibits the generation of M2 macrophages while leaving the generation of classically activated macrophages (M1) intact. Selective deletion of Rictor in macrophages prevents M2 differentiation and clearance of a parasitic helminth infection in mice, and also abrogates the ability of mice to regulate brown fat and maintain core body temperature. Our findings define a role for mTORC2 in macrophages in integrating signals from the immune microenvironment to promote innate type 2 immunity, and also to integrate systemic metabolic and thermogenic responses.
Assuntos
Macrófagos/fisiologia , Alvo Mecanístico do Complexo 2 de Rapamicina/imunologia , Infecções por Strongylida/imunologia , Termogênese/fisiologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Helmintíase Animal/imunologia , Humanos , Imunidade Inata/fisiologia , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nippostrongylus/imunologia , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Proteína Companheira de mTOR Insensível à Rapamicina/imunologia , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Transdução de Sinais/fisiologia , Infecções por Strongylida/parasitologiaRESUMO
Thalidomide is an infamous drug whose use by pregnant women in the middle of last century tragically resulted in serious birth defects. However, as a result of its potent immunomodulatory, anti-inflammatory and antiangiogenic properties, thalidomide may be a potential therapy in many diseases. In recent years, thalidomide has been used effectively to treat various malignancies, including multiple myeloma, myelodysplastic syndromes, renal cell cancer, glioblastoma multiforme and prostate cancer. In addition, thalidomide has also proven effective against other immune-related diseases, including erythema nodosum leprosum and sarcoidosis. Idiopathic pulmonary fibrosis (IPF) is a deadly fibrotic disease with no effective treatment options. However, there is data to suggest that thalidomide may be useful in treating the chronic, disabling cough that accompanies IPF. It remains to be seen whether the immunomodulatory and antiangiogenic properties of thalidomide will also make it a potential therapy against the clinical progression of IPF.
