Modulação multifacetada da função dos monócitos na sepse : comprometimento na apresentação de antígeno, aumento na diferenciação não clássica e na expressão do receptor de fagocitose
Arquivos
Data
2017-09-20
Autores
Mota, Nadijane Valeria Ferreira da 
Orientadores
Salomão, Reinaldo
Tipo
Tese de doutorado
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ISSN da Revista
Título de Volume
Resumo
RESUMO Monócitos e macrófagos são fundamentais na resposta do hospedeiro à sepse, reconhecendo o microrganismo infectante e desencadeando uma resposta inflamatória. Essas funções são, pelo menos em parte, moduladas pela expressão de receptores de superfície celular. Pretendemos caracterizar o fenótipo de monócitos de pacientes sépticos durante o curso da sepse e sua associação com os desfechos clínicos. Sessenta e um pacientes sépticos e 31 voluntários sadios foram incluídos no estudo. As amostras foram obtidas de pacientes na admissão (D0, N = 61) e após 7 (D7, N = 36) e 14 dias de terapia (D14, N = 22). Os monócitos de pacientes sépticos apresentaram expressão diminuída de CD86, HLA-DR, CD200R, CCR2, CXCR2 e CD163 em comparação com monócitos de voluntários sadios. Em contraste, a expressão de PD-1, PD-L1, CD206, CD64 e CD16 estava aumentada nos pacientes. A expressão de HLA-DR, CXCR2, CD64, PD-1 e PD-L1 foi maior nos sobreviventes do que nos não sobreviventes. Houve aumento de expressão de CD86, HLA-DR e CXCR2 em amostras de seguimento; em contraste, CD64 e CD16 GMFI diminuíram ao longo do tempo. Em conclusão, os monócitos de pacientes sépticos apresentam comprometimento da apresentação de antígenos caracterizados por diminuição da expressão de HLA-DR e do coestimulante CD86 e aumento da expressão de PD-1 e PD-L1. Por outro lado, o aumento das atividades inflamatórias e fagocíticas de monócitos pode ser inferido pelo aumento da expressão de CD16 e CD64. Encontramos resultados conflitantes em relação à diferenciação em relação ao fenótipo M2, com aumento da expressão de CD206 e diminuição da expressão de CD163 em monócitos de pacientes sépticos, enquanto o subconjunto de monócitos não clássicos foi demonstrado pelo aumento do CD16hi. HLA-DR, CD64, PD-1 e PD-L1 foram mais expressos nos sobreviventes do que nos não sobreviventes. Palavras-chave: M1 e M2, monócitos clássicos e não-clássicos, fagocitose, imunomodulação, resposta inflamatória.
ABSTRACT Monocytes and macrophages are pivotal in the host-response to sepsis, recognizing the infecting microorganism and triggering an inflammatory response. These functions are, at least in part, modulated by the expression of cell surface receptors. We aimed to characterize the monocyte phenotype from septic patients during an ongoing sepsis process and its association with clinical outcomes. Sixty-one septic patients and 31 healthy volunteers (HV) were enrolled in the study. Samples were obtained from patients at admission (D0, N=61), and after 7 (D7, N=36) and 14 days of therapy (D14, N=22). Monocytes from septic patients presented decreased expression of CD86, HLA-DR, CD200R, CCR2, CXCR2 and CD163 compared with HV monocytes. In contrast, the PD-1, PD-L1, CD206, CD64, and CD16 expression levels were upregulated in patients. HLA-DR, CXCR2, CD64, PD-1, and PD-L1 expression levels were higher in survivors than in non-survivors. Increased CD86, HLA-DR and CXCR2 expression levels were observed in follow-up samples; in contrast, CD64 and CD16 GMFI decreased over time. In conclusion, monocytes from septic patients show antigen presentation impairment as characterized by decreased HLA-DR and co-stimulatory CD86 expression and increased PD-1 and PD-L1 expression. These receptors were higher in survivors than in nonsurvivors. On the other hand, increased monocyte inflammatory and phagocytic activities may be inferred by the increased CD16 and CD64 expression. We found conflicting results regarding differentiation towards the M2 phenotype, with increased CD206 expression and decreased CD163 expression on monocytes from septic patients, while the subset of non-classical monocytes was demonstrated by increased CD16hi. Key words: M1 and M2 monocytes, classical and non-classical monocytes, phagocytosis, immunomodulation, inflammatory response.
ABSTRACT Monocytes and macrophages are pivotal in the host-response to sepsis, recognizing the infecting microorganism and triggering an inflammatory response. These functions are, at least in part, modulated by the expression of cell surface receptors. We aimed to characterize the monocyte phenotype from septic patients during an ongoing sepsis process and its association with clinical outcomes. Sixty-one septic patients and 31 healthy volunteers (HV) were enrolled in the study. Samples were obtained from patients at admission (D0, N=61), and after 7 (D7, N=36) and 14 days of therapy (D14, N=22). Monocytes from septic patients presented decreased expression of CD86, HLA-DR, CD200R, CCR2, CXCR2 and CD163 compared with HV monocytes. In contrast, the PD-1, PD-L1, CD206, CD64, and CD16 expression levels were upregulated in patients. HLA-DR, CXCR2, CD64, PD-1, and PD-L1 expression levels were higher in survivors than in non-survivors. Increased CD86, HLA-DR and CXCR2 expression levels were observed in follow-up samples; in contrast, CD64 and CD16 GMFI decreased over time. In conclusion, monocytes from septic patients show antigen presentation impairment as characterized by decreased HLA-DR and co-stimulatory CD86 expression and increased PD-1 and PD-L1 expression. These receptors were higher in survivors than in nonsurvivors. On the other hand, increased monocyte inflammatory and phagocytic activities may be inferred by the increased CD16 and CD64 expression. We found conflicting results regarding differentiation towards the M2 phenotype, with increased CD206 expression and decreased CD163 expression on monocytes from septic patients, while the subset of non-classical monocytes was demonstrated by increased CD16hi. Key words: M1 and M2 monocytes, classical and non-classical monocytes, phagocytosis, immunomodulation, inflammatory response.
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Citação
MOTA, Nadijane Valeria Ferreira da. Modulação multifacetada da função dos monócitos na sepse: comprometimento na apresentação de antígeno, aumento na diferenciação não clássica e na expressão do receptor de fagocitose. São Paulo, 2017. Tese (Doutorado em Infectologia) - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, 2017.