Bacterial stimulation triggers IRF7-mediated IFN-λ production in hepatocytes to attenuate sepsis.

Interferon lambda (IFN-λ) is produced early by hematopoietic or epithelial cells and acts as a primary mediator of frontline antiviral defense without inducing inflammatory responses. However, whether hepatocytes, rather than immune cells, can secrete IFN-λs to protect against bacterial infection remains unestablished. Here, we demonstrate that hepatocytes secrete IFN-λs in response to bacterial stimulation both in vivo and in vitro, and that this secreted IFN-λs directly inhibits bacterial proliferation. Mechanistically, during in vitro bacterial infection, the upregulation and activation of the transcription factor IRF7 drive type III interferon (IFN-λ) production in hepatocytes through a cascading TLR4 signaling pathway, rather than via RIG-I or MDA5. Importantly, pretreatment with IFN-λs, through interaction with IFNLR1 in hepatocytes, increases the number of dead bacteria, improves systemic outcomes, and enhances survival in septic mice. Furthermore, sepsis patients show increased expression levels of IRF7, IFN-λ2, and IFN-λ3. These findings reveal that IFN-λs function as active mediators against bacterial infection, eliciting a unique antibacterial response to eliminate bacteria. This work further suggests that enhancing IFN-λs production in hepatocytes could serve as a potential therapeutic strategy for sepsis.