RESUMEN
The chemokine SDF-1 alpha (CXC12) and its receptor CXCR4 have been shown to play a role in the development of normal cerebellar cytoarchitecture. We report here that SDF-1 alpha both induces chemotactic responses in granule precursor cells and enhances granule cell proliferative responses to Sonic hedgehog. Chemotactic and proliferative responses to SDF-1 alpha are greater in granule cells obtained from cerebella of animals in the first postnatal week, coinciding with the observed in vivo peak in cerebellar CXCR4 expression. SDF-1 alpha activation of neuronal CXCR4 differs from activation of CXCR4 in leukocytes in that SDF-1 alpha-induced calcium flux is activity dependent, requiring predepolarization with KCl or pretreatment with glutamate. However, as is the case in leukocytes, neuronal responses to SDF-1 alpha are all abolished by pretreatment of granule cells with pertussis toxin, suggesting they occur through G(alpha i) activation. In conclusion, SDF-1 alpha plays a role in two important processes of granule cell maturation - proliferation and migration - assisting in the achievement of appropriate cell number and position in the cerebellar cortex.
Asunto(s)
Cerebelo/citología , Quimiocinas CXC/fisiología , Quimiotaxis/fisiología , Transactivadores/fisiología , Animales , Calcio/metabolismo , División Celular , Polaridad Celular , Cerebelo/metabolismo , Quimiocina CXCL12 , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Femenino , Proteínas Hedgehog , Masculino , Ratones , Ratones Endogámicos BALB C , Ratas , Receptores CXCR4/genética , Transactivadores/metabolismoRESUMEN
Antigen-specific CD4 T helper type 2 (Th2) cells play a pivotal role in the induction of allergic asthma, but the mechanisms regulating their recruitment into the airways are unknown. Signal transducer and activator of transcription factor (Stat)6 is a transcription factor essential for Th2 cell differentiation. Here we show that Stat6 also controls Th2 cell recruitment and effector function in allergic inflammation in vivo. To isolate the role of Stat6 in regulating Th2 cell trafficking and effector function from its role in Th2 cell differentiation, we used a murine model of asthma in which in vitro-differentiated Stat6(+/+) antigen-specific Th2 cells were adoptively transferred into naive Stat6(-/-) and Stat6(+/+) mice followed by aerosol antigen challenge. We found that all of the features of asthma, including Th2 cell accumulation, Th2 and eosinophil-active chemokine production, and airway eosinophilia, mucus production, and hyperresponsiveness seen in Stat6(+/+) mice, were dramatically absent in Stat6(-/)- mice that received Stat6(+/)+ antigen-specific Th2 cells. Our findings establish Stat6 as essential for Th2 cell trafficking and effector function and suggest that interruption of Stat6 signaling in resident cells of the lung is a novel approach to asthma therapy.
Asunto(s)
Transducción de Señal/inmunología , Células Th2/inmunología , Transactivadores/inmunología , Activación Transcripcional , Animales , Antígenos/inmunología , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocinas/genética , Citocinas/genética , Eosinófilos/inmunología , Perfilación de la Expresión Génica , Células Caliciformes/metabolismo , Pulmón/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Moco/metabolismo , Ovalbúmina/inmunología , Factor de Transcripción STAT6 , Transactivadores/genéticaRESUMEN
Monocyte chemoattractant proteins-1 and -5 have been implicated as important mediators of allergic pulmonary inflammation in murine models of asthma. The only identified receptor for these two chemokines to date is the CCR2. To study the role of CCR2 in a murine model of Ag-induced asthma, we compared the pathologic and physiological responses of CCR2(-/-) mice with those of wild-type (WT) littermates following immunization and challenge with OVA. OVA-immunized/OVA-challenged (OVA/OVA) WT and CCR2(-/-) mice developed significant increases in total cells recovered by bronchoalveolar lavage (BAL) compared with their respective OVA-immunized/PBS-challenged (OVA/PBS) control groups. There were no significant differences in BAL cell counts and differentials (i.e., macrophages, PMNs, lymphocytes, and eosinophils) between OVA/OVA WT and CCR2(-/-) mice. Serologic evaluation revealed no significant difference in total IgE and OVA-specific IgE between OVA/OVA WT mice and CCR2(-/-) mice. Lung mRNA expression and BAL cytokine protein levels of IL-4, IL-5, and IFN-gamma were also similar in WT and CCR2(-/-) mice. Finally, OVA/OVA CCR2(-/-) mice developed increased airway hyper-responsiveness to a degree similar to that in WT mice. We conclude that following repeated airway challenges with Ag in sensitized mice, the development of Th2 responses (elevated IgE, pulmonary eosinophilia, and lung cytokine levels of IL-4 and IL5) and the development of airway hyper-responsiveness are not diminished by a deficiency in CCR2.
Asunto(s)
Antígenos/inmunología , Hiperreactividad Bronquial/inmunología , Eosinofilia Pulmonar/inmunología , Receptores de Quimiocina/fisiología , Animales , Especificidad de Anticuerpos , Antígenos/administración & dosificación , Hiperreactividad Bronquial/enzimología , Hiperreactividad Bronquial/genética , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Quimiotaxis de Leucocito/genética , Quimiotaxis de Leucocito/inmunología , Citocinas/metabolismo , Peroxidasa del Eosinófilo , Eosinófilos/enzimología , Inmunoglobulina E/sangre , Inyecciones Intraperitoneales , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovalbúmina/inmunología , Peroxidasas/metabolismo , Eosinofilia Pulmonar/enzimología , Eosinofilia Pulmonar/genética , ARN Mensajero/metabolismo , Receptores CCR2 , Receptores de Quimiocina/deficiencia , Receptores de Quimiocina/genética , RibonucleasasRESUMEN
The generation of an adaptive immune response against intracellular pathogens requires the recruitment of effector T cells to sites of infection. Here we show that the chemokine IP-10, a specific chemoattractant for activated T cells, controls this process in mice naturally infected with Toxoplasma gondii. Neutralization of IP-10 in infected mice inhibited the massive influx of T cells into tissues and impaired antigen-specific T cell effector functions. This resulted in >1000-fold increase in tissue parasite burden and a marked increase in mortality compared to control antibody-treated mice. These observations suggest that IP-10 may play a broader role in the localization and function of effector T cells at sites of Th1 inflammation.