Work

STAT1 drives the immune landscape of murine Toll-like receptor 9-induced liver inflammation

Year: 2025

Type: article

Abstract: Background & aims Persistent activation of Toll-like receptor 9 (TLR9) has been implicated in eliciting a cytokine storm syndrome, leading to systemic and hepatic inflammation in mice and humans. This study investigates the unexplored role of STAT1, a transcription factor in pathogen-driven immune response, in mediating TLR9-induced liver inflammation. Methods We compared clinical, histological and laboratory characteristics (in total 9 parameters) of TLR9-induced liver inflammation between wild-type (WT) mice and STAT1-deficient ( Stat1 -/- ) mice (n = 3-31 mice/condition depending on the parameter measured) and explored their hepatic immune landscape using single-cell CITE-sequencing (total of 36.585 CD45 + liver cells from 4-8 mice/condition. Findings were validated by flow cytometry, treatment with biologicals, ex vivo cell culture, and exploration of publicly available patient datasets. Results Stat1 -/- mice are protected against TLR9-induced inflammation as they do not develop the typical features seen in WT counterparts ( p <0.05-0.0001, depending on the parameter). This protection is associated with the absence of hepatic cycling CD38 + CD8 + T cells, type 2 conventional dendritic cells, and monocytes transitioning into inflammatory macrophages. These cell populations exhibit elevated STAT1 expression and type I and II interferon (IFN) signatures, resembling immune profiles of patients with cytokine storm syndromes and liver inflammation. Ex vivo , type I and II IFNs induce the phenotype of cycling T cells and transitioning monocytes through STAT1 signaling. In vivo, simultaneous treatment with anti-type I and II IFN antibodies in CpG-injected WT mice provided protection against systemic and liver inflammation ( p <0.05-0.001 for 5 mice/condition). Conclusions Type I and II IFN-induced STAT1 activation drives TLR9-induced liver inflammation, and support further exploration of JAK1/2 inhibitors, which indirectly inhibit STAT1 activity, in patients with cytokine storm syndrome and other inflammatory liver disorders. Impact and implications Our study reveals that interferon (IFN)-induced STAT1 signaling is a central mediator of both systemic and hepatic inflammation during a TLR9-induced cytokine storm. Based on these findings, we support the therapeutic use of JAK1/2 inhibitors, such as ruxolitinib and baricitinib, which indirectly suppress STAT1 activity, in patients with cytokine storm syndromes and inflammatory liver disorders to alleviate both systemic and hepatic symptoms. Notably, our data also highlight the promise of direct STAT1 inhibition as a more and potentially refined approach for intervention.

Source: JHEP Reports

DOI: 10.1016/j.jhepr.2025.101668