Fibrinogen-like protein 2 deficiency inhibits virus-induced fulminant hepatitis through abrogating inflammatory macrophage activation

ARTICLE HIGHLIGHTS

Research background

Viral fulminant hepatitis (VFH) is a devastating syndrome that pathologically caused by excessive activation of both innate and adaptive immunity. However, the extent of contribution of innate immunity in VFH is not well defined. Macrophage polarization have been implicated in host defense and the pathogenesis of various hepatic diseases. Fibrinogen-like protein 2 (FGL2) can be induced robustly and exclusively in macrophages in response to cytokines or viral infection. Exploring their roles in VFH can greatly improve our understanding of the disease and thus seek the therapeutic approaches.

Research motivation

Hepatic macrophages are attractive therapeutic targets because their functions can be inhibited or augmented to alter disease outcomes. A better understanding of their biological properties and immunologic function in liver homeostasis and pathology may pave the way for new diagnostic and therapeutic approaches for liver failure or other liver diseases.

Research objectives

To evaluate the role of Fgl2 in the reconstitution of hepatic macrophages during VFH progression by the VFH mouse model.

Research methods

Liver sections of liver failure patients and controls were immuno-stained for macrophages examination. Murine hepatitis virus strain 3 (MHV-3) was used to induce VFH experimental model in wild type and Fgl2-/- mice. Adoptive transfer or depletion of macrophages were employed to assess liver damage and hepatic macrophages alteration. Signal cascade induced by LPS or MHV-3 were detected in macrophages.

Research results

Infiltrated MoMFs is a major source of hepatic inflammation during VFH progression. Fgl2 expression on macrophages prompts and enhances the inflammatory phenotype of hepatic macrophages, which breaks the previous understanding that the mechanism of Fgl2 during VFH is generally considered to be procoagulant activity.

Research conclusions

We revealed for the first time that pro-inflammatory monocyte-derived macrophages (MoMFs) infiltration is critical event for hepatic inflammatory accumulation and subsequent liver damage during virus-induced hepatitis progression and Fgl2 is required for maintaining the pro-inflammatory hepatic macrophages phenotype.

Research perspectives

Macrophages are ‘keystones’ of liver architecture in both homeostasis and disease. The development of potential therapies highly depends on a fundamental knowledge about the mechanisms that trigger the polarization and control the fate of hepatic macrophages. We believe that a better understanding of the specific mechanisms underlying macrophages participation in diseases will definitely result in the increased efficacy of these therapies.