RESUMO
Marginal zone (MZ) B cells produce a first wave of antibodies for protection from blood-borne pathogens. However, the role of MZ B cells in inflammatory responses has not been elucidated. Here we show that MZ B cells produce pro-inflammatory cytokines, such as interleukin-6 (IL-6), and exacerbate systemic inflammatory responses to lipopolysaccharide (LPS). After intravenous injection of LPS or E. coli, mice deficient in MZ B cells or IL-6 only in MZ B cells have attenuated systemic inflammatory responses and prolonged survival compared with wild-type mice. LPS directly stimulates MZ B cells via Toll-like receptor 4 (TLR4) and MyD88 pathways for IL-6 production. Furthermore, TLR4 requires physical and functional association with Fcα/µR (CD351) for its oligomer formation, NF-κB signalling and IL-6 production from MZ B cells; this association is responsible for systemic inflammatory responses and endotoxic shock. These results reveal a pro-inflammatory role of MZ B cells in endotoxic shock.
Assuntos
Linfócitos B/metabolismo , Interleucina-6/metabolismo , Receptores Fc/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Linfócitos B/efeitos dos fármacos , Infecções por Escherichia coli/fisiopatologia , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptores Fc/genética , Choque Séptico/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptor 4 Toll-Like/genéticaRESUMO
Epithelial tissues continually undergo apoptosis. Commensal organisms that inhabit the epithelium influence tissue homeostasis, in which regulatory T cells (Treg cells) have a central role. However, the physiological importance of epithelial cell apoptosis and how the number of Treg cells is regulated are both incompletely understood. Here we found that apoptotic epithelial cells negatively regulated the commensal-stimulated proliferation of Treg cells. Gut commensals stimulated CX3CR1(+)CD103(-)CD11b(+) dendritic cells (DCs) to produce interferon-ß (IFN-ß), which augmented the proliferation of Treg cells in the intestine. Conversely, phosphatidylserine exposed on apoptotic epithelial cells suppressed IFN-ß production by the DCs via inhibitory signaling mediated by the cell-surface glycoprotein CD300a and thus suppressed Treg cell proliferation. Our findings reveal a regulatory role for apoptotic epithelial cells in maintaining the number of Treg cell and tissue homeostasis.
Assuntos
Apoptose/imunologia , Epiderme/imunologia , Células Epiteliais/imunologia , Microbioma Gastrointestinal/imunologia , Interferon beta/imunologia , Mucosa Intestinal/imunologia , Mucosa Respiratória/imunologia , Linfócitos T Reguladores/imunologia , Alérgenos/toxicidade , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/citologia , Colo/imunologia , Células Dendríticas/imunologia , Dermatite Alérgica de Contato/etiologia , Dermatite Alérgica de Contato/imunologia , Dermatite Alérgica de Contato/patologia , Sulfato de Dextrana/toxicidade , Células Epidérmicas , Citometria de Fluxo , Imuno-Histoquímica , Mucosa Intestinal/citologia , Células de Langerhans/imunologia , Pulmão/citologia , Pulmão/imunologia , Camundongos , Camundongos Knockout , Ovalbumina/toxicidade , Reação em Cadeia da Polimerase em Tempo Real , Receptores Imunológicos/genética , Mucosa Respiratória/citologia , Infecções por Salmonella/imunologia , Salmonella typhimuriumRESUMO
DAP12, an immunoreceptor tyrosine-based activation motif-bearing adapter protein, is involved in innate immunity mediated by natural killer cells and myeloid cells. We show that DAP12-deficient mouse B cells and B cells from a patient with Nasu-Hakola disease, a recessive genetic disorder resulting from loss of DAP12, showed enhanced proliferation after stimulation with anti-IgM or CpG. Myeloid-associated immunoglobulin-like receptor (MAIR) II (Cd300d) is a DAP12-associated immune receptor. Like DAP12-deficient B cells, MAIR-II-deficient B cells were hyperresponsive. Expression of a chimeric receptor composed of the MAIR-II extracellular domain directly coupled to DAP12 into the DAP12-deficient or MAIR-II-deficient B cells suppressed B cell receptor (BCR)-mediated proliferation. The chimeric MAIR-II-DAP12 receptor recruited the SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) after BCR stimulation. DAP12-deficient mice showed elevated serum antibodies against self-antigens and enhanced humoral immune responses against T cell-dependent and T cell-independent antigens. Thus, DAP12-coupled MAIR-II negatively regulates B cell-mediated adaptive immune responses.
Assuntos
Imunidade Adaptativa/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos B/imunologia , Lipodistrofia/imunologia , Osteocondrodisplasias/imunologia , Receptores de Células Matadoras Naturais/imunologia , Proteínas Recombinantes de Fusão/imunologia , Panencefalite Esclerosante Subaguda/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Eletroforese em Gel de Poliacrilamida , Citometria de Fluxo , Vetores Genéticos , Humanos , Lentivirus , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 6/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Receptores de Células Matadoras Naturais/deficiência , Receptores de Imunoglobulina Polimérica/deficiência , Receptores de Imunoglobulina Polimérica/genética , Receptores de Imunoglobulina Polimérica/imunologia , Receptores de Imunoglobulina Polimérica/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
Neutrophils play a central role in host defenses against infectious microbial pathogens. However, molecular basis for their triggering signals has been incompletely understood. Here, we show molecular and functional characteristics of myeloid-associated immunoglobulin-like receptor (MAIR)-IV. MAIR-IV was preferentially expressed on neutrophils in the peripheral blood, bone marrow, peritoneal cavity and spleen. MAIR-IV physically associates with immunoreceptor tyrosine based activating motif (ITAM)-bearing adaptor FcRgamma chain. Cross-linking MAIR-IV with anti-MAIR-IV monoclonal antibody significantly induced secretion of proinflammatory cytokines TNF-alpha and IL-6 from neutrophils. Thus, MAIR-IV may regulate activation of neutrophils and play an important role for innate immunity.