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IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans

Fawaz Alzaid1, Floriane Lagadec2, Miguel Albuquerque2

  • 1Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 1138, Sorbonne Universités, UPMC Université Paris 06; Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot; and Centre de Recherche des Cordeliers, Paris, France.

JCI Insight
|December 13, 2016
PubMed

Insights

Interferon regulatory factor 5 (IRF5) drives liver inflammation and fibrosis by activating macrophages. Inhibiting IRF5 protects against liver damage and fibrogenesis, offering a potential therapeutic target for liver disease.

Area of Science:

  • Immunology
  • Hepatology
  • Molecular Biology

Background:

  • Hepatic fibrosis results from liver inflammation, macrophage activation, and leukocyte accumulation.
  • Hepatic macrophages are crucial in liver homeostasis and the pathogenesis of liver injury and fibrogenesis.
  • Interferon regulatory factor 5 (IRF5) is a key transcription factor in macrophage activation during inflammation.

Purpose of the Study:

  • To investigate the role of IRF5 in liver macrophages in the context of hepatic fibrosis.
  • To determine if IRF5 modulates hepatocyte survival and fibrogenesis.

Main Methods:

  • Analysis of IRF5 expression in liver macrophages from human patients with liver fibrosis (NASH, HCV).
  • Correlation of IRF5 levels with clinical markers of liver damage.
  • Assessment of hepatic fibrosis in myeloid cell-specific IRF5 knockout (MKO) mice under metabolic or toxic stress.
  • Transcriptional analysis of macrophages from IRF5 MKO mice.

Main Results:

  • IRF5 was significantly induced in liver macrophages of human subjects with fibrosis.
  • IRF5 expression correlated positively with liver damage markers (transaminases, bilirubin).
  • IRF5 MKO mice were protected from induced hepatic fibrosis.
  • IRF5-deficient macrophages exhibited immunosuppressive and antiapoptotic properties.
  • IRF5 MKO mice showed enhanced hepatocyte survival and protection from fibrogenesis.

Conclusions:

  • IRF5 plays a critical role in mediating hepatocyte death and liver fibrosis.
  • IRF5 orchestrates a pro-inflammatory network in liver macrophages contributing to fibrogenesis.
  • Targeting IRF5 presents a promising therapeutic strategy for fibroinflammatory liver diseases.

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