Toll-Like Receptor-7 (TLR7) Signaling Promotes Non-Alcoholic Steatohepatitis by Inhibiting Regulatory T Cells in Mice.

Toll-like receptor 7 (TLR7) signaling regulates the production of type I 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 non-alcoholic 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/β receptor-1 (IFNAR1)-deficient, and Treg cell-depleted (DEREG) mice. TLR7-deficient and IFNAR1-deficient mice were more protective to steatohepatitis than WT mice. Interestingly, both TNFα and type I IFN promoted apoptosis of Treg cells involved in the prevention of NASH. Indeed, DEREG mice had aggravated steatohepatitis compared with WT mice. Finally, treatment with IRS661, 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 TLR7-Treg cell axis might be used as a novel therapeutic strategy to treat NASH.