Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection

Abstract

Hepatitis B virus is a major cause of chronic liver inflammation worldwide. Innate and adaptive immune responses work together to restrain or eliminate hepatitis B virus in the liver. Compromised or failed adaptive immune response results in persistent virus replication and spread. How to promote antiviral immunity is a research focus for hepatitis B virus prevention and therapy. In this study, we investigated the role of macrophages in the regulation of antiviral immunity. We found that F4/80 + CD206 + CD80 lo/+ macrophages were a particular hepatic macrophage subset that expressed amphiregulin in our mouse hepatitis B virus infection model. CD206 + macrophage-derived amphiregulin promoted the immunosuppressive activity of intrahepatic regulatory T cells, demonstrated by higher expression of CTLA-4, ICOS, and CD39, as well as stronger inhibition of antiviral function of CD8 + T cells. Amphiregulin-neutralizing antibody diminished the effect of CD206 + macrophages on regulatory T cells. In addition, we found that CD206 + macrophage-derived amphiregulin activated mammalian target of rapamycin signaling in regulatory T cells, and this mammalian target of rapamycin activation was essential for promotion of regulatory T cell activity by CD206 + macrophages. Adoptive transfer of CD206 + macrophages into hepatitis B virusinfected mice increased cytoplasmic hepatitis B virus DNA in hepatocytes and also increased serum hepatitis B surface antigen. The antiviral activity of CD8 + T cells was decreased after macrophage transfer. Therefore, our research indicated that amphiregulin produced by CD206 + macrophages plays an important role in modulating regulatory T cell function and subsequently restrains the antiviral activity of CD8 + T cells. Our study offers new insights into the immunomodulation in hepatitis B virus infection.

Role of Tim-3 in hepatitis B virus infection: An overview

“…Macrophages can be classified into 2 types: M1 and M2. M1 cells contribute to HBV clearance, whereas M2 cells impair the host immune response, promote HBV infection and accelerate tumorigenesis [45,46] . In addition, HBV tends to promote M2 polarization [6,7] .…”

Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet‐induced mouse model of nonalcoholic steatohepatitis

“…Third, the phenotype of intrahepatic macrophages was altered following treatment with high-dose CVC. The frequency of macrophages expressing proinflammatory M1 markers was significantly lower after 4 weeks of high-dose CVC, and by 14 weeks we observed an increase in intrahepatic macrophages displaying the anti-inflammatory M2 marker CD206, which is known to have anti-inflammatory properties (e.g., secreting amphiregulin to promote immunosuppressive activity by intrahepatic regulatory T cells and inhibiting cytolytic CD81 T cells (22) ) and antifibrotic properties (resorption of extracellular matrix from hepatic scar tissue (19,20) ). Krenkel and colleagues (23) recently reported the enrichment of CD2061 macrophages in livers of mice fed an alternate NASHinducing diet, the Western diet, and treated with CVC for 5 weeks following a 9-week dietary lead-in period, adding credibility to our findings.…”

The Correlation of CD206, CD209, and Disease Severity in Behçet’s Disease with Arthritis

“…CD206 was highly expressed with significance in active BD patients with cutaneous symptoms (49.7 ± 35.2%) compared to inactive BD patients (4.7 ± 3.1%) ( p = 0.007) and HCs (7.4 ± 0.8%) ( p = 0.02). It is known that CD206 facilitates viral infections such as Dengue virus [28], hepatitis B virus [29], lymphadenopathy associated virus [30], and human immunodeficiency virus [31]. In collagen induced arthritis, CD206 was seen in the inflamed joints by micro-computed tomography imaging [32].…”