Interleukins-27 Aggravates Liver Injury by Impairing the Antimicrobial Response of Macrophages via the Promotion of Mitochondrial Dysfunction in the Context of Sepsis.

Background and Aims: Plasma interleukin (IL)-27 is an important mediator of acute hepatic injury (AHI) associated with sepsis. Mitochondria contribute to the proper regulation of macrophage phagocytosis. In this study, we investigated the effect of IL-27 on mitochondrial function and the antimicrobial response of macrophages in sepsis-associated AHI. Methods: Wild-type (WT) and IL-27 receptor WSX-1 deficient (IL-27R^-/-) mice underwent cecal ligation and puncture (CLP). The severity of hepatic injury, inflammatory cytokine levels, hepatic pyroptosis, and bacterial load in the liver and blood were assessed 24 h after CLP. In vitro, RAW264.7 cells and peritoneal macrophages were treated with lipopolysaccharide (LPS) and/or IL-27. The phagocytosis and killing functions of macrophages were detected. Mitochondrial function and mitophagy were detected using western blot, glutathione (GSH)/malondialdehyde (MDA) content measurement, fluorescence staining, and JC-1 staining in vivo and in vitro. After treatment with nicotinamide mononucleotide (NMN, NAD + precursor), a pharmacologic agent that improves mitochondrial function, the inflammatory response, hepatic injury, and hepatic pyroptosis were assessed. Results: IL-27R^-/- mice exhibited a marked reduction in hepatic injury, pyroptosis (based on cleaved GSDMD and cleaved Caspases 1 protein levels), and systemic inflammation (based on serum IL-6, IL-10, and TNF-α levels) compared to WT mice following CLP. After CLP, mice lacking IL-27R displayed significantly higher bacterial clearance and greater local infection control. Subsequent studies demonstrated that IL-27 directly impaired the LPS-induced bacterial phagocytosis, killing capacity, and mitochondrial function of macrophages. Finally, enhanced mitochondrial function using NMN in vivo significantly alleviated pathological liver injury and inflammation. Conclusions: These findings indicated that IL-27 impairs the bacterial phagocytosis capacity of macrophages by aggravating mitochondrial dysfunction to aggravate AHI during sepsis.