Toll-Like Receptor-7 Signaling Promotes Nonalcoholic Steatohepatitis by Inhibiting Regulatory T Cells in Mice.
Am J Pathol
; 188(11): 2574-2588, 2018 11.
Article
en En
| MEDLINE
| ID: mdl-30125542
ABSTRACT
Toll-like receptor 7 (TLR7) signaling regulates the production of type 1 interferons (IFNs) and proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, implicated in the control of regulatory T (Treg) cell activity. However, the mechanistic interplay between TLR7 signaling and Treg cells in nonalcoholic steatohepatitis (NASH) has not been elucidated. Our aim was to clarify the role of TLR7 signaling in the pathogenesis of NASH. Steatohepatitis was induced in wild-type (WT), TLR7-deficient, IFN-α/ß receptor 1-deficient, and Treg cell-depleted mice. TLR7-deficient and IFN-α/ß receptor 1-deficient mice were more protective to steatohepatitis than WT mice. Of interest, both TNF-α and type 1 IFN promoted apoptosis of Treg cells involved in the prevention of NASH. Indeed, Treg cell-depleted mice had aggravated steatohepatitis compared with WT mice. Finally, treatment with immunoregulatory sequence 661, an antagonist of TLR7, efficiently ameliorated NASH in vivo. These results demonstrate that TLR7 signaling can induce TNF-α production in Kupffer cells and type I IFN production in dendritic cells. These cytokines subsequently induce hepatocyte death and inhibit Treg cells activities, leading to the progression of NASH. Thus, manipulating the TLR7-Treg cell axis might be used as a novel therapeutic strategy to treat NASH.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Células Dendríticas
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Glicoproteínas de Membrana
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Linfocitos T Reguladores
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Receptor Toll-Like 7
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Enfermedad del Hígado Graso no Alcohólico
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Macrófagos del Hígado
Límite:
Animals
Idioma:
En
Revista:
Am J Pathol
Año:
2018
Tipo del documento:
Article