RESUMO
BACKGROUND AND AIMS: The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH). APPROACH AND RESULTS: We found that in SH, γδT cells are recruited to the liver by C-C chemokine receptor (CCR) 2, CCR5, and nucleotide-binding oligomerization domain-containing protein 2 signaling and are skewed toward an interleukin (IL)-17A+ phenotype in an inducible costimulator (ICOS)/ICOS ligand-dependent manner. γδT cells exhibit a distinct Vγ4+ , PD1+ , Ly6C+ CD44+ phenotype in SH. Moreover, γδT cells up-regulate both CD1d, which is necessary for lipid-based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL-17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet-induced SH and accelerates disease resolution. CONCLUSIONS: We demonstrate that hepatic γδT cells exacerbate SH, independent of IL-17 expression, by mitigating conventional CD4+ T-cell expansion and modulating their inflammatory program by CD1d-dependent vascular endothelial growth factor expression.
Assuntos
Imunidade Adaptativa/fisiologia , Fígado Gorduroso/etiologia , Imunidade Inata/fisiologia , Linfócitos Intraepiteliais/fisiologia , Animais , Feminino , Masculino , CamundongosAssuntos
Infecções por HIV/microbiologia , Pneumocystis carinii/isolamento & purificação , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Síndrome da Imunodeficiência Adquirida/microbiologia , Adulto , Estudos Transversais , DNA Fúngico/isolamento & purificação , Feminino , Humanos , Masculino , Peru , Pneumocystis carinii/genética , Reação em Cadeia da Polimerase/métodosAssuntos
Adulto , Feminino , Humanos , Masculino , Infecções por HIV/microbiologia , Pneumocystis carinii/isolamento & purificação , Peru , DNA Fúngico/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Estudos Transversais , Síndrome da Imunodeficiência Adquirida/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Pneumocystis carinii/genéticaRESUMO
Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFαlow CD206hi phenotype downregulating mTOR, IL-8 signaling and oxidative phosphorylation. Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis.