RESUMO
Alternatively activated macrophages (AAM) play a crucial role in type 2 immunity. Mice deficient in ST2, a receptor for the latest member of the IL-1 family, IL-33, have impaired type 2 immune responses. We therefore reasoned that IL-33/ST2 signaling may be involved in the differentiation and activation of AAM during airway inflammation. We report here that IL-33 changed the quiescent phenotype of alveolar macrophages toward an AAM phenotype that expressed mannose receptor, IL-4Ralpha, and produced high levels of CCL24 and CCL17 in an IL-13-dependent manner during IL-33-induced airway inflammation. Neutralization of AAM-derived CCL24 led to an amelioration of IL-33-induced eosinophilia in the lungs. Moreover, depletion of alveolar macrophages reduced IL-33-induced airway inflammation. Additionally, the attenuated OVA-induced airway inflammation in ST2(-/-) mice was associated with a decrease in AAM differentiation. In vitro, IL-33 amplified IL-13-induced polarization of alveolar- and bone marrow-derived macrophage toward an AAM phenotype by increasing the expression of arginase I, Ym1, as well as the production of CCL24 and CCL17. IL-13/IL-4Ralpha signaling was crucial for IL-33-driven AAM amplification by inducing the expression of ST2L. Finally, we showed that IL-33 was more abundantly expressed in the lung epithelial cells of asthma patients than those from healthy controls, suggesting that IL-33 may be involved in lung macrophage activation in clinical asthma. Taken together, we demonstrate here that IL-33/ST2 plays a significant role in the amplification of AAM polarization and chemokine production which contribute to innate and Ag-induced airway inflammation.
Assuntos
Polaridade Celular/imunologia , Células Epiteliais/imunologia , Inflamação/imunologia , Interleucinas/imunologia , Macrófagos Alveolares/imunologia , Receptores de Interleucina/imunologia , Adulto , Animais , Asma/imunologia , Asma/metabolismo , Quimiocina CCL17/imunologia , Quimiocina CCL17/metabolismo , Quimiocina CCL24/imunologia , Quimiocina CCL24/metabolismo , Eosinofilia/imunologia , Células Epiteliais/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-13/imunologia , Interleucina-13/metabolismo , Interleucina-33 , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-4/metabolismo , Interleucinas/metabolismo , Pulmão/imunologia , Pulmão/patologia , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Pessoa de Meia-Idade , Ovalbumina/imunologia , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Interleucina-1/imunologia , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-4/genética , Receptores de Interleucina-4/imunologia , Receptores de Interleucina-4/metabolismo , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Transdução de Sinais/imunologiaRESUMO
Regulatory T cells play a major role in modulating the immune response. However, most information on these cells centers on autoimmunity, and there is also considerable controversy on the functional characteristics of these cells. Here we provide direct in vitro and in vivo evidence that CD4+CD25+ regulatory T cells inhibit the differentiation and functions of both Th1 and Th2 cells. Importantly, CD4+CD25+ T cells suppressed the disease development of Leishmania major infection in SCID mice reconstituted with naive CD4+CD25- T cells. Furthermore, CD4+CD25+ T cells inhibited the development of colitis induced by both Th1 and Th2 cells in SCID mice. Our results therefore document that CD4+CD25+ regulatory T cells suppress both Th1 and Th2 cells and that these regulatory T cells have a profound therapeutic potential against diseases induced by both Th1 and Th2 cells in vivo.
