Scavenger receptor a restrains T-cell activation and protects against concanavalin A-induced hepatic injury

Authors

  • Daming Zuo,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA
    2. VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
    3. VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA
    4. Department of Immunology, Southern Medical University, Guangzhou, China
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  • Xiaofei Yu,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA
    2. VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
    3. VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Chunqing Guo,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA
    2. VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
    3. VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Hongxia Wang,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA
    2. VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
    3. VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Jie Qian,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA
    2. VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
    3. VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Huanfa Yi,

    1. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA
    2. VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
    3. VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Xiao Lu,

    1. Department of Immunology, Southern Medical University, Guangzhou, China
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  • Zhi-Ping Lv,

    1. The Key Laboratory of Molecular Biology, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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  • John R. Subjeck,

    1. Department of Cellular Stress Biology, Roswell Park Cancer Institute, Buffalo, NY
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  • Huiping Zhou,

    1. Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Arun J. Sanyal,

    1. Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Zhengliang Chen,

    Corresponding author
    1. Department of Immunology, Southern Medical University, Guangzhou, China
    • Department of Human & Molecular Genetics, PO Box 980033, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
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  • Xiang-Yang Wang

    Corresponding author
    1. Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA
    2. VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA
    3. VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA
    • Department of Immunology, Southern Medical University, Guangzhou, 510515, China
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  • Potential conflict of interest: Dr. Sanyal consults for and received grants from Salix. He also received grants from Exhalenz, Genentech, Gilead, Ikaria, and Intercept. He also received royalties from Uptodate.

  • Supported in part by National Institutes of Health (NIH) Grants CA154708, CA129111, American Cancer Society Scholarship (to X.Y.W.), NCI Cancer Center Support Grants to VCU Massey Cancer Center P30 CA16059, and Natural Science Foundation of China 30972679 (to Z.C.). X.Y.W. is a Harrison Endowed Scholar at the VCU Massey Cancer Center.

Abstract

Negative feedback immune mechanisms are essential for maintenance of hepatic homeostasis and prevention of immune-mediated liver injury. We show here that scavenger receptor A (SRA/CD204), a pattern recognition molecule, is highly up-regulated in the livers of patients with autoimmune or viral hepatitis, and of mice during concanavalin A (Con A)-induced hepatitis (CIH). Strikingly, genetic SRA ablation strongly sensitizes mice to Con A-induced liver injury. SRA loss, increased mortality and liver pathology correlate with excessive production of IFN-γ and heightened activation of T cells. Increased liver expression of SRA primarily occurs in mobilized hepatic myeloid cells during CIH, including CD11b+Gr-1+ cells. Mechanistic studies establish that SRA on these cells functions as a negative regulator limiting T-cell activity and cytokine production. SRA-mediated protection from CIH is further validated by adoptive transfer of SRA+ hepatic mononuclear cells or administration of a lentivirus-expressing SRA, which effectively ameliorates Con A-induced hepatic injury. Also, CIH and clinical hepatitis are associated with increased levels of soluble SRA. This soluble SRA displays a direct T-cell inhibitory effect and is capable of mitigating Con A-induced liver pathology. Conclusion: Our findings demonstrate an unexpected role of SRA in attenuation of Con A-induced, T-cell-mediated hepatic injury. We propose that SRA serves as an important negative feedback mechanism in liver immune homeostasis, and may be exploited for therapeutic treatment of inflammatory liver diseases. (HEPATOLOGY 2013)

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