RESUMO
Triggering receptor expressed on myeloid cells (TREM)-1 is a cell surface molecule expressed on neutrophils and monocytes implicated in the propagation of the inflammatory response. To further characterize the function of this molecule in different phases of the immune response, we examined TREM-1 in the context of host defense against microbial pathogens. In primary human monocytes TREM-1 activation did not trigger innate antimicrobial pathways directed against intracellular Mycobacterium tuberculosis, and only minimally improved phagocytosis. However, activation of TREM-1 on monocytes did drive robust production of proinflammatory chemokines such as macrophage inflammatory protein-1alpha and IL-8. Engagement of TREM-1 in combination with microbial ligands that activate Toll-like receptors also synergistically increased production of the proinflammatory cytokines TNF-alpha and GM-CSF, while inhibiting production of IL-10, an anti-inflammatory cytokine. Expression of TREM-1 was up-regulated in response to TLR activation, an effect further enhanced by GM-CSF and TNF-alpha but inhibited by IL-10. Functionally, primary monocytes differentiated into immature dendritic cells following activation through TREM-1, evidenced by higher expression of CD1a, CD86, and MHC class II molecules. These cells had an improved ability to elicit T cell proliferation and production of IFN-gamma. Our data suggest that activation of TREM-1 on monocytes participates during the early-induced and adaptive immune responses involved in host defense against microbial challenges.
Assuntos
Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/microbiologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores Imunológicos/fisiologia , Atividade Bactericida do Sangue/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Quimiocinas/biossíntese , Quimiocinas/metabolismo , Citocinas/biossíntese , Citocinas/fisiologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Sinergismo Farmacológico , Humanos , Inflamação/prevenção & controle , Ligantes , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/fisiologia , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/imunologia , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/fisiologia , Receptores Imunológicos/biossíntese , Receptores Imunológicos/sangue , Subpopulações de Linfócitos T/imunologia , Receptores Toll-Like , Receptor Gatilho 1 Expresso em Células Mieloides , Regulação para Cima/imunologiaRESUMO
Leprosy presents as a clinical and immunological spectrum of disease. With the use of gene expression profiling, we observed that a distinction in gene expression correlates with and accurately classifies the clinical form of the disease. Genes belonging to the leukocyte immunoglobulin-like receptor (LIR) family were significantly up-regulated in lesions of lepromatous patients suffering from the disseminated form of the infection. In functional studies, LIR-7 suppressed innate host defense mechanisms by shifting monocyte production from interleukin-12 toward interleukin-10 and by blocking antimicrobial activity triggered by Toll-like receptors. Gene expression profiles may be useful in defining clinical forms of disease and providing insights into the regulation of immune responses to pathogens.
Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hanseníase Virchowiana/classificação , Hanseníase Virchowiana/genética , Hanseníase Tuberculoide/classificação , Hanseníase Tuberculoide/genética , Algoritmos , Análise por Conglomerados , Contagem de Colônia Microbiana , Citocinas/genética , Citocinas/metabolismo , Genes de Imunoglobulinas , Humanos , Imunidade Celular , Imunidade Inata , Hanseníase Virchowiana/imunologia , Hanseníase Virchowiana/fisiopatologia , Hanseníase Tuberculoide/imunologia , Hanseníase Tuberculoide/fisiopatologia , Macrófagos Alveolares/microbiologia , Glicoproteínas de Membrana/imunologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Análise de Componente Principal , Receptores de Superfície Celular/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores Toll-Like , Regulação para CimaRESUMO
Leprosy presents as a clinical and immunological spectrum of disease. With the use of gene expression profiling, we observed that a distinction in gene expression correlates with and accurately classifies the clinical form of the disease. Genes belonging to the leukocyte immunoglobulin-like receptor (LIR) family were significantly up-regulated in lesions of lepromatous patients suffering from the disseminated form of the infection. In functional studies, LIR-7 suppressed innate host defense mechanisms by shifting monocyte production from interleukin-12 toward interleukin-10 and by blocking antimicrobial activity triggered by Toll-like receptors. Gene expression profiles may be useful in defining clinical forms of disease and providing insights into the regulation of immune responses to pathogens.