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IL-4 treatment induces apoptosis of blood monocytes and proliferation of reparative macrophages to resolve liver injury.

ABSTRACT: IL-4 can have significant therapeutic benefit in many injury settings, but its mechanism of action is unclear. Here, we show that, in a model ofCCl4-mediatedacuteliver injury, exogenous IL-4 caused adramatic shift from recruited Ly6Chimonocytes to an abundance of monocyte-derived macrophages. This shift in macrophage dynamics was associated with accelerated clearance of necrotic tissue and enhanced hepatocyte regeneration that required IL-4 receptor-signalling to leukocytes. IL-4 did not alter monocyte recruitment or differentiation but instead stimulated monocyte apoptosis and acted on previously-recruited macrophages to drive proliferation and pro-repair characteristics, including expression of key genes involved in dismantling necrotic tissue. Further scRNA-seq analysis of the impact of IL-4 on all hepatic myeloid lineages revealed injury and cell-type specific responses. Together, our data reveal a novel pathway by which IL-4 alters the composition and functional specification of injury-associated myeloid cells and resolves injury in the liver.

ORGANISM(S): Mus musculus

PROVIDER: GSE242411 | GEO | 2026/02/20

REPOSITORIES: GEO

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Project description:Background: Immune cell-driven inflammation is a key mediator of metabolic dysfunction-associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P1) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages into the liver. Methods: The LyzMCre approach was used to generate myeloid cell-specific knockout mice, termed S1pr1MKO. Littermate S1pr1loxp/loxp mice were used as wild-type (WT) controls. MASH was established by feeding mice a high-fat, fructose, and -cholesterol (FFC) diet for 24 weeks which leads to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry. Results: Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in FFC-fed S1pr1MKO compared to WT. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of FFC-fed S1pr1MKO mice compared to WT. Gene ontology pathway analysis revealed a significant suppression of the peroxisome proliferator-activated receptor gamma (PPARγ) and mitogen activated protein kinase (MAPK) pathways in S1pr1MKO consistent with attenuated MASH in mice. Conclusion: Deletion of S1P1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.

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IL-4 treatment induces apoptosis of blood monocytes and proliferation of reparative macrophages to resolve liver injury.

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