Cholesterol accumulation on dendritic cells reverses chronic hepatitis B virus infection-induced dysfunction

Published in Healthcare & Nursing
Cholesterol accumulation on dendritic cells reverses chronic hepatitis B virus infection-induced dysfunction
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Chronic hepatitis B (CHB) infection remains a serious public health problem worldwide. CHB is difficult to cure mainly because of the immuno-suppressive microenvironment formed in the liver of patients with CHB with a high proportion of regulatory T cells, myeloid-derived suppressor cells, and dysfunctional antigen-presenting cells (APCs). As professional APCs, dendritic cells (DCs) represent a link between innate and adaptive immune responses. Previous studies report that DCs from CHB patients display impaired antigen-presenting and migration capacities relative to those from healthy donors (HDs). However, the mechanisms involved in DC dysfunction induced by CHB have not been fully clarified.

Cholesterol is an indispensable lipid molecule that plays an important role in multiple biological processes, including the formation of lipid rafts, major histocompatibility complex (MHC) molecules, T cell receptors (TCRs), B-cell receptors, and Toll-like receptors. The cholesterol level in immune cells reflects the dynamic balance among biosynthesis, uptake, efflux, and esterification. Previous study showed that inhibiting cholesterol esterification reduces the accumulation of neutral lipid droplets by driving translocation of esterified cholesterol to the plasma membrane. Free cholesterol in the plasma membrane is a critical structural component of lipid rafts, which can be identified by the presence of cholera toxin B subunit (CTxB). Lipid rafts act as cholesterol-enriched specialized microdomains and play a crucial role in membrane trafficking and signaling transduction, as well as manipulating immune cell phenotype and function. These findings confirm the essential role of cholesterol in regulating immune cell activation; however, it remains unclear whether CHB affects cholesterol levels on DCs and subsequent dysfunction of DC-mediated anti-HBV immune responses. In our recent work in Cellular & Molecular Immunology (https://www.nature.com/articles/s41423-022-00939-1), we investigated the relationship between cholesterol levels and CHB.

To clarify whether CHB affects cholesterol metabolism and lipid raft formation on DCs, we isolated PBMCs from healthy donors and patients with immune-tolerant CHB, and found CHB significantly reduced levels of free cholesterol, lipid rafts, and LDLR on DCs compared to HDs, accompanied with altered cholesterol metabolism in PBMCs; however, CHB did not affect free cholesterol levels on CD4+ or CD8+ T cells or NK cells. We also used the HBV-carrier mouse model to confirm these findings. Consistently, we found that HBV-carrier mice showed decreased cholesterol levels on DCs from PBMCs compared to WT mice, accompanied by significantly downregulated levels of lipid rafts and LDLR. Additionally, we found a positive correlation between cholesterol and lipid raft levels on DCs, with confocal microscopy revealing the co-localization of lipid rafts and membrane cholesterol in DCs. To elucidate the HBV components contributing to this phenomenon, we incubated mouse BMDCs with plasma from patients with CHB and HDs, along with different doses of HBsAg and HBeAg, we found that application of HBsAg or serum from patients with CHB was able to suppress free cholesterol levels and lipid raft formation on DCs, but the depletion of HBsAg resisted CHB plasma-mediated effects on BMDCs, indicating the ability of HBsAg to decrease cholesterol biosynthesis and/or LDLR-mediated endocytosis in CHB-infected DCs. We determined that CHB, especially the presence of HBsAg, reduced free cholesterol levels and suppressed lipid raft formation on DCs. This might represent a new mechanism involved in CHB-induced immune tolerance. Interestingly, treatment with lipophilic statins promoted cholesterol accumulation and restored lipid raft formation on DCs, with this possible due to the combined effects of changes in cellular cholesterol synthesis, esterification, and absorption. Significantly, cholesterol accumulation on DCs enhanced antigen presentation and triggered efficient anti-HBV immune responses accompanied by the signs of development of memory responses against HBV re-challenge. Identifying novel strategies to promote DC functions to restore exhausted HBV-specific CD8+ T cells and improve their effector function could efficiently eliminate HBV and achieve a functional cure. Given the importance of DCs in initiating and maintaining HBV-specific T cell responses, these findings suggest that maintaining high levels of free cholesterol on DCs might promote lipid raft formation and thereby enhance antigen presentation and T cell priming.  These results highlight an important role for cholesterol in DC dysfunction during CHB and suggest a novel strategy for increasing therapeutic vaccine efficacy against HBV.

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