IL-33 Alleviates Sepsis-Induced Liver Injury by Regulating the NF-κB/BCL-2 Pathway

Interleukin-33 (IL-33), a tissue-derived alarmin released during sterile and infectious stress, modulates inflammatory responses in an organ-specific manner. Although IL-33 is implicated in hepatic pathophysiology, its functional mechanism in sepsis-induced liver injury (SILI) remains insufficiently characterized.

SILI was modeled in vivo via cecal ligation and puncture (CLP) and in vitro using lipopolysaccharide (LPS)-stimulated primary hepatocytes. The multimodal evaluations included oxidative stress analysis, inflammatory cytokine measurements, liver functional biomarker analysis, and histomorphological studies. IL-33 signaling was investigated by combining transcriptomic pathway analysis with pharmacological interventions with soluble ST2 decoy receptor (sST2) and ST2-neutralizing (anti-ST2) antibodies. The SILI model dynamically increased the IL-33 level.

Exogenous IL-33 conserved liver architecture, improved function, and reduced both inflammation and oxidative damage. Critically, blocking IL-33/ST2 signaling with an anti-ST2 antibody or sST2 eliminated the protective effect of IL-33, worsening hepatocellular damage. Mechanistic investigations revealed that IL-33/ST2 stimulation reduced NF-κB pathway activity, improved BCL-2 expression, and inhibited caspase-3-- mediated apoptosis. The lack of the antiapoptotic effects of IL-33 on NF-κB pathway activation validated its regulatory axis specificity.

This study identifies IL-33/ST2-NF-κB-BCL-2 as a key axis mitigating hepatocyte apoptosis in SILI. IL-33-based therapies may offer dual control of inflammation and cell death, though clinical translation requires temporal optimization.

Our results suggest that the pharmacologically targeted IL-33/ST2-NF-κB-BCL-2 pathway decreases sepsis-induced hepatocyte apoptosis. These findings indicate that IL-33-based treatments may be feasible for treating SILI and that this axis coordinates cytoprotection by concurrently controlling inflammatory signals and apoptotic processes.