{
  "abstract": "Background Kupffer cells and monocyte-derived macrophages (MoMs) are difficult to study in human primary biliary cholangitis (PBC) even though they reflect a dynamic hepatic immune population.Objective We aim to investigate the role of hepatic macrophage and its therapeutic potential in human PBC and murine autoimmune cholangitis.Design Phenotypic analysis of hepatic macrophages in patients with PBC and dnTGFβRII mice model was performed by single-cell RNA sequencing, flow cytometry and immunohistochemistry. Depletion of hepatic macrophages and inhibition of MoMs were performed in murine autoimmune cholangitis. Lyz2-Cre-mediated Atg5 knockout mice and co-culture experiments were applied to explore the role and mechanism of macrophage autophagy in autoimmune cholangitis. Therapeutic intervention was performed using nanoparticle-capsuled small interfering RNA against Atg5.Results Kupffer cells from patients with PBC and dnTGFβRII mice upregulate genes associated with inflammatory responses and exhibit increased autophagy. Further, macrophage-specific knockout of Atg5 leads to reduction of inflammation and bile duct damage. We propose that the mechanism of this modulation is secondary to decreased activation of pathogenic CD8+ T cells. Indeed, Kupffer cells maintain CD8+ T cell tolerance through expression of inducible nitric oxide synthase (iNOS) and generation of NO. Increased autophagy resulted in degradation of iNOS in Kupffer cells and abrogated their suppressive activity against CD8+ T cells. Finally, we report that targeted downregulation of Kupffer cell autophagy in vivo using cationic lipid-assisted nanoparticles encapsulating siRNA against Atg5 leads to reduction of liver inflammation and bile duct damage.Conclusion Macrophage autophagy promotes autoimmune cholangitis and strongly supports this pathway as a potential therapeutic target.",
  "authors": [
    {
      "affiliations": [
        "Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Gunagzhou, Guangdong, China",
        "Department of Rheumatology and Immunology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, Guangdong, China"
      ],
      "name": "Pan-Yue Luo"
    },
    {
      "affiliations": [
        "Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China",
        "Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Min Ma"
    },
    {
      "affiliations": [
        "Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Gunagzhou, Guangdong, China",
        "Department of Rheumatology and Immunology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China",
        "School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, Guangdong, China"
      ],
      "name": "Meng-Chu Liu"
    },
    {
      "affiliations": [
        "Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Ye-Hui Wu"
    },
    {
      "affiliations": [
        "Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Jie Long"
    },
    {
      "affiliations": [
        "Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Meng-Xing Huang"
    },
    {
      "affiliations": [
        "Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Si-Yu Yang"
    },
    {
      "affiliations": [
        "Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Gunagzhou, Guangdong, China"
      ],
      "name": "Tian-Tian Da"
    },
    {
      "affiliations": [
        "Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Tokushima Prefecture, Japan"
      ],
      "name": "Koichi Tsuneyama"
    },
    {
      "affiliations": [
        "Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Qiao Li"
    },
    {
      "affiliations": [
        "Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Haosheng Jin"
    },
    {
      "affiliations": [
        "Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Zhi-Bin Zhao"
    },
    {
      "affiliations": [
        "School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, Guangdong, China"
      ],
      "name": "Jun Wang"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China"
      ],
      "name": "Xiong Ma"
    },
    {
      "affiliations": [
        "Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Sacramento, California, USA"
      ],
      "name": "Merrill Eric Gershwin"
    },
    {
      "affiliations": [
        "State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital of Air Force Military Medical University, Xi’an, Shaanxi, China"
      ],
      "name": "Ying Han"
    },
    {
      "affiliations": [
        "Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Zhe-Xiong Lian"
    },
    {
      "affiliations": [
        "Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Liang Li"
    }
  ],
  "title": "Autophagy of Kupffer cells modulates CD8+ T cell activation in primary biliary cholangitis",
  "uid": "8b60f9ec-ad24-58c0-b706-717cb775a113"
}