Taurocholic acid inhibits the response to interferon-α therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function

Cellular and Molecular Immunology - Tập 18 Số 2 - Trang 461-471 - 2021
Zhen Xun1, Jinpiao Lin1, Qingqing Yu2, Can Liu1, Jinlan Huang1, Hongyan Shang1, Jianhui Guo1, Yuchen Ye2, Wennan Wu1, Yongbin Zeng1, Songhang Wu1, Siyi Xu3, Tianbin Chen1, Jing Chen4, Qishui Ou1
1Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
2First Clinical College, Fujian Medical University, Fuzhou, China
3Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
4Center of Liver Diseases, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China

Tóm tắt

AbstractPegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3+CD8+ T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3+CD8+ T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3+CD8+ T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment.

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Tài liệu tham khảo

Tang, L. S. Y., Covert, E., Wilson, E. & Kottilil, S. Chronic hepatitis B infection: a review. JAMA 319, 1802–1813 (2018).

Yuen, M.-F. et al. Hepatitis B virus infection. Nat. Rev. Dis. Prim. 4, 1–20 (2018).

Terrault, N. A. et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67, 1560–1599 (2018).

Lampertico, P. et al. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol. 67, 370–398 (2017).

Tsai, K. N., Kuo, C. F. & Ou, J. J. Mechanisms of hepatitis B virus persistence. Trends Microbiol. 26, 33–42 (2018).

Bertoletti, A. & Ferrari, C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut 61, 1754–1764 (2012).

Tjwa, E. T., van Oord, G. W., Hegmans, J. P., Janssen, H. L. & Woltman, A. M. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J. Hepatol. 54, 209–218 (2011).

Maini, M. K. et al. Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology 117, 1386–1396 (1999).

Yang, F. et al. Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection. PLoS Pathog. 15, e1007690 (2019).

Kelly, B. & O’Neill, L. A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 25, 771–784 (2015).

Ganeshan, K. & Chawla, A. Metabolic regulation of immune responses. Annu. Rev. Immunol. 32, 609–634 (2014).

Jia, W., Xie, G. & Jia, W. Bile acid–microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat. Rev. Hepatol. Gastroenterol. 15, 111–128 (2017).

Guo, C. et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity 45, 802–816 (2016).

Hu, M. M. et al. Virus-induced accumulation of intracellular bile acids activates the TGR5-beta-arrestin-SRC axis to enable innate antiviral immunity. Cell Res. 29, 193–205 (2019).

Chang, K. O. & George, D. W. Bile acids promote the expression of hepatitis C virus in replicon-harboring cells. J. Virol. 81, 9633–9640 (2007).

Schupp, A. K. et al. Bile acids act as soluble host restriction factors limiting cytomegalovirus replication in hepatocytes. J. Virol. 90, 6686–6698 (2016).

Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019).

Ma, C. et al. Gut microbiome–mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360, eaan5931 (2018).

Song, X. et al. Microbial bile acid metabolites modulate gut RORgamma(+) regulatory T cell homeostasis. Nature 577, 410–415 (2020).

Kim, H. Y., Cho, H. K., Choi, Y. H., Lee, K. S. & Cheong, J. Bile acids increase hepatitis B virus gene expression and inhibit interferon-alpha activity. FEBS J. 277, 2791–2802 (2010).

Reese, V. C., Oropeza, C. E. & McLachlan, A. Independent activation of hepatitis B virus biosynthesis by retinoids, peroxisome proliferators, and bile acids. J. Virol. 87, 991–997 (2013).

Reese, V. C., Moore, D. D. & McLachlan, A. Limited effects of bile acids and small heterodimer partner on hepatitis B virus biosynthesis in vivo. J. Virol. 86, 2760–2768 (2012).

Lacaille, F. & Paradis, K. The immunosuppressive effect of ursodeoxycholic acid a comparative in vitro study on human peripheral blood mononuclear cells. Hepatology 18, 165–172 (1993).

Podevin, P. et al. Effect of cholestasis and bile acids on interferon-induced 2’,5’-adenylate synthetase and NK cell activities. Gastroenterology 108, 1192–1198 (1995).

Chen, H. et al. Variants in STAT4 associated with cure of chronic HBV infection in HBeAg-positive patients treated with pegylated interferon-alpha. Clin. Gastroenterol. Hepatol. 18, 196–204 (2020).

Li, W. et al. KIR3DS1/HLA-B Bw4-80Ile genotype is correlated with the IFN-alpha therapy response in hepatitis B e antigen-positive chronic hepatitis B. Front. Immunol. 8, 1285–1295 (2017).

Yang, D. et al. A mouse model for HBV immunotolerance and immunotherapy. Cell Mol. Immunol. 11, 71–78 (2014).

Brandl, K. et al. Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis. J. Hepatol. 69, 396–405 (2018).

Jiao, N. et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut 67, 1881–1891 (2018).

Kakiyama, G. et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J. Hepatol. 58, 949–955 (2013).

Gao, Q. et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell 179, 561–577 (2019).

Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P. & Salazar-Mather, T. P. Natural killer cells in antiviral defense function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).

Gibbert, K., Schlaak, J. F., Yang, D. & Dittmer, U. IFN-α subtypes: distinct biological activities in anti-viral therapy. Br. J. Pharmacol. 168, 1048–1058 (2013).

Hu, J., Lin, Y. Y., Chen, P. J., Watashi, K. & Wakita, T. Cell and animal models for studying hepatitis B virus infection and drug development. Gastroenterology 156, 338–354 (2019).

Kwaa, A. K. R., Talana, C. A. G., Blankson, J. N. & Silvestri, G. Interferon alpha enhances NK cell function and the suppressive capacity of HIV-specific CD8+T cells. J. Virol. 93, e01541–01518 (2019).

Hervas-Stubbs, S. et al. Effects of IFN-α as a signal-3 cytokine on human naïve and antigen-experienced CD8+ T cells. Eur. J. Immunol. 40, 3389–3402 (2010).

RO, PodevinP. et al. Bile acids modulate the interferon signalling pathway. Hepatology 29, 1840–1847 (1999).

Sugita, T. et al. Analysis of the serum bile acid composition for differential diagnosis in patients with liver disease. Gastroenterol. Res. Pract. 2015, 1–10 (2015).

Rehermann, B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat. Med. 19, 859–868 (2013).

Zeng, Y. et al. Gut microbiota dysbiosis in patients with hepatitis B virus–induced chronic liver disease covering chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. J. Viral Hepat. 27, 143–155 (2020).

Chang, K. O. et al. Bile acids are essential for porcine enteric calicivirus replication in association with down-regulation of signal transducer and activator of transcription 1. Proc. Natl Acad. Sci. U. S. A. 101, 8733–8738 (2004).

Stark George, R. & Darnell James, E. The JAK-STAT pathway at twenty. Immunity 36, 503–514 (2012).

Calmus, Y. et al. Immunosuppressive properties of chenodeoxycholic and ursodeoxycholic acids in the mouse. Gastroenterology 103, 617–621 (1992).

Anwer, M. S. Intracellular signaling by bile acids. J. Bio-Sci. 20, 1–23 (2014).

Bertoletti, A. & Ferrari, C. Adaptive immunity in HBV infection. J. Hepatol. 64, S71–S83 (2016).

Maini, M. K. & Burton, A. R. Restoring releasing or replacing adaptive immunity in chronic hepatitis B. Nat. Rev. Gastroenterol. Hepatol. 16, 662–675 (2019).

Sun, C. et al. TGF-beta1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog. 8, e1002594 (2012).

Hempfling, W., Dilger, K. & Beuers, U. Systematic review: ursodeoxycholic acid—adverse effects and drug interactions. Alimentary Pharmacol. Ther. 18, 963–972 (2003).

Sorrentino, G. et al. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration. Gastroenterology 159, 956–968.e8 (2020).

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Cellular and Molecular Immunology

Tập 18 Số 2

461-471

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