Interleukin-19 ameliorates drug-induced liver injury by limiting proinflammatory macrophage infiltration via SUMOylation of C/EBPβ.

Acetaminophen (APAP) overdose is the leading cause of acute liver failure in Western countries. However, the inflammatory mechanisms underlying APAP-induced liver injury (AILI) remain poorly understood. Interleukin (IL)-19 exerts its biological effects through binding to the IL-20 receptor complex (IL-20R1/IL-20R2). This study aimed to investigate the role of IL-19 in AILI. Il19-deficient mice and myeloid cell-specific Il20r2 knockout mice were generated and subjected to AILI. Single-cell RNA sequencing (ScRNA-seq) was performed to analyze hepatic macrophage subsets. Il19-deficient mice exhibited increased susceptibility to AILI, accompanied by a distinct transcriptional profile and a marked increase in proinflammatory macrophage infiltration. Treatment with recombinant IL-19 significantly suppressed proinflammatory macrophage infiltration and attenuated AILI. scRNA-seq analysis revealed that myeloid cell-specific Il20r2 deficiency exacerbated AILI and was associated with increased infiltration of S100A8/A9+ proinflammatory macrophages. Mechanistically, IL-19 downregulated CCAAT/enhancer-binding protein β (C/EBPβ) expression in macrophages by promoting its post-translational SUMOylation. This reduced C/EBPβ-mediated transcription of proinflammatory genes, including those regulating S100A8/A9 expression, thereby ameliorating AILI. IL-19 plays a key role in limiting proinflammatory macrophage infiltration and thereby ameliorates early-stage AILI. These findings suggest that IL-19 may represent a promising therapeutic target for AILI. Although IL-19 signals through the IL-20 receptor complex (IL-20R1/IL-20R2), its role in liver disease remains incompletely understood. Here, we show that IL-19 protects against APAP-induced liver injury by restricting the infiltration of S100A8/A9+ proinflammatory macrophages. Both Il19-deficient mice and myeloid cell-specific Il20r2-deficient mice displayed increased susceptibility to APAP hepatotoxicity and enhanced accumulation of S100A8/A9+ proinflammatory macrophages. Mechanistically, IL-19 promotes C/EBPβ SUMOylation, thereby suppressing proinflammatory gene expression. These findings identify IL-19 as a potential therapeutic target for acute liver injury.