The dual role of recombinant IL-33 in acute liver failure: hepatoprotection versus lethal systemic inflammation

Interleukin-33 (IL-33), a member of the IL-1 family, participates in immune regulation and tissue repair, but its role in acute liver failure (ALF) remains unclear. This study investigated the effects and mechanisms of recombinant IL-33 in a concanavalin A (Con A)-induced murine ALF model.

Female C57BL/6J mice received Con A (10 mg/kg) with or without recombinant IL-33 (1 μg/mouse, 2 h before Con A). Liver injury was evaluated by serum transaminases and histology. Cytokines were measured by ELISA, qRT-PCR, and Luminex assays. Hepatic Tregs were analyzed by flow cytometry, macrophage infiltration and polarization by multiplex immunofluorescence, and hepatocyte proliferation and STAT3 activation by immunohistochemistry. Survival was assessed after lethal Con A challenge (25 mg/kg).

Endogenous IL-33 was markedly upregulated during Con A-induced liver injury. Recombinant IL-33 pretreatment reduced serum ALT and AST levels and attenuated liver injury, but paradoxically increased mortality following lethal Con A challenge. Recombinant IL-33 increased serum IL-1β, MCP-1, and TNF-α, elevated hepatic IL-1β and MCP-1 expression, and promoted macrophage infiltration and M1 polarization. It also increased Ki-67 and PD-1 expression in Tregs, particularly within the ST2⁺ Treg subset, and enhanced hepatic Ki-67 expression and STAT3 phosphorylation.

Recombinant IL-33 exerts context-dependent effects in ALF. While it alleviates hepatocellular injury, modulates the proliferative and activation phenotypes of Tregs, and promotes hepatocyte regeneration, it may also exacerbate systemic inflammation by promoting macrophage M1 polarization, thereby contributing to increased mortality.