RESUMO
Although much is described about the molecules involved in neutrophil migration from circulation into tissues, less is known about the molecular mechanisms that regulate neutrophil entry into lymph nodes (LNs) draining a local inflammatory site. In this study, we investigated neutrophil migration toward LNs in a context of inflammation induced by immunization of BALB/c mice with OVA emulsified in CFA. We demonstrated that neutrophils can enter LNs of OVA/CFA-immunized mice not only via lymphatic vessels but also from blood, across high endothelial venules. By adoptive transfer experiments, we showed that this influx was dependent on an inflammatory-state condition and previous neutrophil stimulation with OVA/anti-OVA immune complexes. Importantly, we have demonstrated that, in the migratory pattern to LNs, neutrophils used L-selectin and P-selectin glycoprotein ligand-1, macrophage-1 Ag and LFA-1 integrins, and CXCR4 to get access across high endothelial venules, whereas macrophage-1 Ag, LFA-1, and CXCR4 were involved in their trafficking through afferent lymphatics. Strikingly, we found that stimulation with immune complexes significantly upregulated the expression of sphingosine-1-phosphate receptor 4 on neutrophils, and that treatment with the sphingosine-1-phosphate agonist FTY720 altered neutrophil LN-homing ability. These findings summarized in this article disclose the molecular pattern that controls neutrophil recruitment to LNs.
Assuntos
Complexo Antígeno-Anticorpo/imunologia , Doenças do Sistema Imunitário/imunologia , Transtornos Leucocíticos/imunologia , Linfonodos/imunologia , Neutrófilos/imunologia , Transferência Adotiva , Animais , Movimento Celular/imunologia , Feminino , Cloridrato de Fingolimode , Imunossupressores/farmacologia , Inflamação/imunologia , Selectina L/imunologia , Linfonodos/citologia , Vasos Linfáticos/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Lisofosfolipídeos/agonistas , Antígeno de Macrófago 1/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/transplante , Selectina-P/imunologia , Propilenoglicóis/farmacologia , Receptores CXCR4/imunologia , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/agonistas , Esfingosina/análogos & derivados , Esfingosina/farmacologiaRESUMO
Urethane is a chemical carcinogen which causes lung tumorigenesis in mice with similarities to human adenocarcinoma (AC). The sphingosine 1-phosphate agonist FTY720 administered to mice in doses above 5 mg/kg/day has been able to prevent hepatocellular carcinoma and bladder cancer. We used BALB/c mice in urethane-induced lung cancer model to investigate the effects of a lower dose of FTY720 (1 mg/kg/day). The benefits of FTY720 were associated with the time point of the compound administration. FTY720 30 Group presented lower incidence and smaller area of lung nodules, decreased PCNA and increased Caspase-3 expressions. The findings in FTY720 0 Group (nodule multiplicity and area, PCNA expression) were similar to Urethane Group suggesting that the administration of the compound at early time point did not affect lung tumor development. FTY720 90 Group presented the biggest nodule area which was associated with increased PCNA and decreased Caspase-3 expressions. FTY720 (30 days and 90 days) administration decreased CD4 + splenocytes and blood lymphocytes which caused opposite effects in lung tumor development - impairment and improvement respectively.In conclusion, FTY720 in low dose did not provide lung tumor inhibition in mice but its administration 30 days after the chemical carcinogen (Urethane) injection was associated with impaired tumor development.