ABSTRACT
Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease, mediated by pathogenic T helper 17 (Th17) cells. However, the therapeutic effect is accompanied by the fluctuation of the proportion and function of Th17 cells, which prompted us to find the key regulator of Th17 differentiation in MS. Here, we demonstrated that the triggering receptor expressed on myeloid cells 2 (TREM-2), a modulator of pattern recognition receptors on innate immune cells, was highly expressed on pathogenic CD4-positive T lymphocyte (CD4+ T) cells in both patients with MS and experimental autoimmune encephalomyelitis (EAE) mouse models. Conditional knockout of Trem-2 in CD4+ T cells significantly alleviated the disease activity and reduced Th17 cell infiltration, activation, differentiation, and inflammatory cytokine production and secretion in EAE mice. Furthermore, with Trem-2 knockout in vivo experiments and in vitro inhibitor assays, the TREM-2/zeta-chain associated protein kinase 70 (ZAP70)/signal transducer and activator of transcription 3 (STAT3) signal axis was essential for Th17 activation and differentiation in EAE progression. In conclusion, TREM-2 is a key regulator of pathogenic Th17 in EAE mice, and this sheds new light on the potential of this therapeutic target for MS.
Subject(s)
Animals , Humans , Mice , CD4-Positive T-Lymphocytes/pathology , Cell Differentiation , Encephalomyelitis, Autoimmune, Experimental/metabolism , Mice, Inbred C57BL , Multiple Sclerosis , Th1 Cells/pathologyABSTRACT
Existe atualmente grande discussao a respeito do valor da imunoterapia nas doencas alergicas, mas, a luz de novos conhecimentos a respeito do sistema imune e particularmente das populacoes de linfocitos TH1 e TH2 e do tipo predominante de resposta que provocam, e necessario uma reavaliacao desta imunoterapia e especialmente da sua precocidade para os 2 ou 3 primeiros anos de vida. Discute-se o valor da regulacao das populacoes TH1 e TH2, os fatores que influenciam nesta regulacao, o papel dos virus respiratorios, a profilaxia e o controle ambiental e a intervencao com imunoterapia precoce