RESUMEN
Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.
Asunto(s)
Microambiente Celular/inmunología , Células Dendríticas/inmunología , Inmunidad Innata , Mitocondrias/inmunología , Especies Reactivas de Oxígeno/inmunología , Respuesta de Proteína Desplegada/inmunología , Animales , Microambiente Celular/genética , Ciclo del Ácido Cítrico/genética , Ciclo del Ácido Cítrico/inmunología , Células Dendríticas/patología , Hexoquinasa/genética , Hexoquinasa/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Ratones , Ratones Noqueados , Mitocondrias/genética , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Respuesta de Proteína Desplegada/genética , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/inmunologíaRESUMEN
Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. Presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of NASH patients before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed NAFLD reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity upon LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intra-hepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy.
Asunto(s)
Hígado/inmunología , Enfermedad del Hígado Graso no Alcohólico/genética , Transcripción Genética , Animales , Dieta Alta en Grasa , Redes Reguladoras de Genes , Humanos , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/terapiaRESUMEN
In the version of this article initially published, ANR grant ANR-16-RHUS-0006 to author Joel T. Haas was not included in the Acknowledgements. The error has been corrected in the HTML and PDF versions of the article.