The CCL2-CCR2-Ly6c + macrophage axis in PegIFNα-2b therapy for chronic hepatitis B

Area of Science:

• Immunology
• Hepatology
• Virology

Background:

• Interferon (IFN) is a key treatment for chronic hepatitis B (CHB), but its efficacy varies widely.
• The precise mechanisms by which IFN-α exerts therapeutic effects through innate immunity, especially macrophages, remain incompletely understood.

Purpose of the Study:

• To investigate the role of the CCL2-CCR2-macrophage signaling axis in mediating the antiviral activity of interferon-α (IFN-α) therapy for CHB.
• To elucidate the specific mechanisms through which this axis contributes to IFN-α's therapeutic benefits.

Main Methods:

• Analysis of a public single-cell dataset (GSE237519) to examine the hepatic immune microenvironment after long-term IFN-α treatment.
• Utilized a humanized mouse model (huIFNAR) infected with AAV-HBV, treated with pegylated interferon-α-2b (PegIFNα-2b) combined with CCR2 antagonism or macrophage depletion.
• Employed single-cell RNA sequencing (scRNA-seq), flow cytometry, immunohistochemistry, and serum HBV biomarker detection to assess the CCL2-CCR2-macrophage axis's role.

Main Results:

• Long-term IFN treatment altered hepatic macrophage populations and activated CCL signaling.
• Macrophage depletion reduced IFN's suppression of HBV DNA replication and HBsAg decline.
• CCR2 antagonism diminished PegIFNα-2b's antiviral efficacy by inhibiting monocyte recruitment and disrupting the CCL2-CCR2 axis, impairing Ly6c+ macrophage differentiation and intercellular communication.

Conclusions:

• The CCL2-CCR2-Ly6c+ macrophage axis is identified as a critical immunoregulatory pathway in IFN therapy for CHB.
• This axis orchestrates macrophage recruitment, differentiation, and crosstalk, mediating the antiviral effects of PegIFNα-2b.
• Targeting this axis presents a potential strategy for enhancing IFN-based immunotherapies for CHB.