Hepatocyte CCL9 Drives Fibrogenic Immune Signaling : Hepatology | Apr 2026

Introduction

Liver Fibrosis results from persistent hepatic injury, chronic inflammation and activation of hepatic stellate cells (HSCs). Chemokine-mediated immune recruitment is central to fibrogenesis, yet many inflammatory pathways governing hepatocyte–immune–stromal interactions remain incompletely characterized. This mechanistic study investigated the role of hepatocyte-derived Ccl9, the murine homolog of human CCL15, in regulating hepatic inflammation and fibrosis progression.

Problem Statement

Although inflammatory chemokines are known contributors to liver injury, the specific role of hepatocyte-derived Ccl9 in coordinating immune cell recruitment, macrophage polarization and direct stellate cell activation during fibrosis has remained unclear.

Summary

Using multiple murine fibrosis models including carbon tetrachloride exposure, bile duct ligation and diet-induced steatohepatitis, investigators demonstrated marked upregulation of Ccl9 expression within fibrotic livers. Injured hepatocytes represented the primary cellular source of Ccl9, while the transcription factor Myc was identified as a major upstream regulator driving its induction during hepatic injury.

Functional studies using hepatocyte-specific Ccl9 knockout mice showed substantial attenuation of fibrosis and liver injury across all experimental models. Ccl9 deletion reduced inflammatory infiltration, hepatic macrophage accumulation and neutrophil recruitment, supporting a central role for hepatocyte-derived chemokine signaling in orchestrating fibrogenic inflammation. Similar antifibrotic effects were achieved using Ccl9-neutralizing antibodies, highlighting potential translational therapeutic relevance.

Mechanistically, Ccl9 promoted recruitment and activation of inflammatory macrophages through the Ccr1 receptor pathway. Importantly, Ccl9 shifted macrophage polarization toward a proinflammatory M1 phenotype and amplified inflammatory cytokine signaling within injured liver tissue. Beyond immune modulation, the study demonstrated that Ccl9 directly activated hepatic stellate cells through a distinct intracellular signaling cascade.

Specifically, Ccl9–Ccr1 signaling recruited Myh9 and enhanced Wnt pathway activation via Myh9-mediated ubiquitination of Gsk3β, thereby promoting stellate cell activation and extracellular matrix production. This dual role — simultaneously amplifying inflammatory immune signaling and directly stimulating fibrogenic stellate pathways — positions Ccl9 as a particularly important upstream mediator of fibrosis progression.

The findings are especially notable because they identify hepatocytes not merely as passive injury targets but as active immunoregulatory drivers of fibrogenesis through chemokine secretion. The study also strengthens the growing concept that fibrosis progression depends on tightly integrated hepatocyte–immune–mesenchymal signaling networks rather than isolated stellate cell activation alone.

Overall, this translational work identifies the hepatocyte-derived Ccl9/Ccr1 axis as a major promoter of liver fibrosis progression through coordinated immune recruitment, macrophage polarization and direct HSC activation. The data support therapeutic targeting of Ccl9 signaling as a potentially promising antifibrotic strategy across diverse chronic liver diseases.