HIV-induced monocyte and macrophage perturbations driving liver fibrogenesis

HIV诱导的单核细胞和巨噬细胞扰动驱动肝纤维化

• 批准号: 10647917
• 负责人: Nadia Alatrakchi
• 金额: $ 65.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10647917
• 关键词: Anti-Inflammatory Agents; Antiinflammatory Effect; Automobile Driving; B-Lymphocytes; Biological Assay; Blocking Antibodies; Cell Line; Cells; Chronic; Cicatrix; Data; Environment; Excision; Exposure to; Fatty Acids; Fine needle aspiration biopsy; Grant; HIV; HIV Infections; HIV/HCV; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammatory; Kupffer Cells; Light; Liver; Liver Fibrosis; Liver diseases; Molecular Target; Myeloid Cells; Myeloid-derived suppressor cells; Natural Immunity; Pathogenesis; Pathologic; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Play; Population; Proteins; Proteomics; Public Health; Recombinants; Residual state; Role; S100A9 gene; Serum; Testing; Viral; Viral Antigens; Virus; antiretroviral therapy; cell type; cellular targeting; chronic liver disease; cohort; comparative; fibrogenesis; immune activation; in vivo; liver injury; macrophage; macrophage product; monocyte; nonalcoholic steatohepatitis; peripheral blood; scavenger receptor; simple steatosis; systemic inflammatory response; transcriptomics

Abstract Liver disease in patients with HIV infection remains a major public health problem despite effective combination antiretroviral therapy (cART), and cART does not fully reverse HIV-related immune activation. Monocyte and macrophage populations play a central role in inflammation and liver pathogenesis and are triggered during HIV, even in the absence of known causes of liver injury. Chronically activated monocytes/macrophages polarize to a spectrum of pro-inflammatory and anti-inflammatory states which contribute to hepatic fibrogenesis. Our preliminary study of the immune cell landscape in liver fine needles aspirates (FNAs) and corresponding peripheral blood mononuclear cells (PBMCs) from patients with HIV infection prior to and during the first 6- months of cART, uncovered 1) the presence of monocytic myeloid-derived suppressor cells (M-MDSC) that persist on cART despite virus control; and 2) increased serum levels of sCD5L, the soluble scavenger receptor secreted by macrophages, which does not decrease on cART. Both M-MDSCs and sCD5L are described to expand in inflammatory conditions, have anti-inflammatory effects, and recently have been shown to promote the anti-inflammatory/profibrotic macrophage phenotype. We have also observed similar findings in HCV infection and NASH. Together these findings may constitute a causative mechanism driving a profibrotic milieu, particularly in the liver. We hypothesize that HIV-induced M-MDSCs and CD5L remain upregulated on suppressive ART and contribute to a persistent profibrotic liver milieu. Using patient derived human material, we will test this hypothesis through the following aims: (1) Define the role of M-MDSCs in driving fibrogenesis in the setting of HIV infection. Using M-MDSCs from healthy donor PBMC pre/post exposure to HIV, we will assess whether HIV-induced M-MDSCs drive the profibrotic profile in macrophages and hepatic stellate cells (HSCs) and will explore contributory mechanisms using blocking/silencing functional assays. Additionally, to confirm whether M-MDSCs persist in suppressed HIV in vivo, we will comprehensively characterize the transcriptomic/proteomic single cell landscape in HIV patient PBMCs, pre-ART/at several timepoints of cART. (2) Define the role of CD5L in driving fibrogenesis in the setting of HIV infection. Using recombinant (r)CD5L we will determine whether this product promotes the profibrogenic profile in HIV-triggered healthy donor monocyte derived macrophages and M-MDSCs as well as in HIV-exposed primary HSCs and/or hepatocytes. Additionally, we will determine if plasma from HIV patients (pre/during cART) with or without CD5L blocking antibodies induces a profibrotic phenotype. (3) Determine how HIV impacts M-MDSC and CD5L function in the setting of co-existing liver disease. We will comparatively explore M-MDSCs and CD5L by single cell transcriptomics/proteomics in cohorts of patients with HIV, HIV/HCV, HIV/HBV and HIV/NASH in liver FNAs, and we will validate suggested profibrogenic mechanisms in vitro using primary/cell lines co-exposed to these insults. Together these studies will shed great light on the contribution of monocytes and macrophages to HIV-associated liver disease.

抽象的 尽管有效联合治疗，艾滋病毒感染者的肝病仍然是一个主要的公共卫生问题 抗逆转录病毒疗法（cART），并且 cART 不能完全逆转 HIV 相关的免疫激活。单核细胞和 巨噬细胞群在炎症和肝脏发病机制中发挥着核心作用，并在 HIV、 即使没有已知的肝损伤原因。长期激活的单核细胞/巨噬细胞极化为 一系列促炎和抗炎状态，有助于肝纤维化。我们的 肝脏细针抽吸物 (FNA) 中免疫细胞景观的初步研究和相应的 HIV 感染患者在前 6 周之前和期间的外周血单核细胞 (PBMC) 经过数月的 cART，发现 1) 单核细胞骨髓源性抑制细胞 (M-MDSC) 的存在 尽管病毒得到控制，仍坚持使用 cART； 2) 血清 sCD5L（可溶性清道夫受体）水平升高 由巨噬细胞分泌，在 cART 上不会减少。 M-MDSC 和 sCD5L 均被描述为 在炎症条件下扩大，具有抗炎作用，最近已被证明可以促进 抗炎/促纤维化巨噬细胞表型。我们在 HCV 中也观察到类似的发现 感染和 NASH。这些发现共同构成了促纤维化环境的致病机制， 特别是在肝脏中。我们假设 HIV 诱导的 M-MDSC 和 CD5L 在 抑制性 ART 并导致持续的促纤维化肝环境。使用源自患者的人体材料，我们 将通过以下目标检验这一假设：（1）定义 M-MDSC 在驱动纤维形成中的作用 HIV 感染的环境。使用来自健康捐赠者 PBMC 暴露于 HIV 之前/之后的 M-MDSC，我们将评估 HIV 诱导的 M-MDSC 是否会驱动巨噬细胞和肝星状细胞 (HSC) 的促纤维化特征 并将使用阻断/沉默功能测定来探索贡献机制。另外，为了确认 M-MDSCs是否在体内持续抑制HIV，我们将全面表征 HIV 患者 PBMC 中 ART 前/cART 几个时间点的转录组/蛋白质组单细胞景观。 (2) 定义 CD5L 在 HIV 感染情况下驱动纤维形成的作用。使用重组 (r)CD5L 我们 将确定该产品是否促进 HIV 触发的健康供体单核细胞的促纤维化特征 衍生的巨噬细胞和 M-MDSC 以及暴露于 HIV 的原代 HSC 和/或肝细胞。此外， 我们将确定来自 HIV 患者的血浆（在 cART 之前/期间）在有或没有 CD5L 阻断抗体的情况下是否会诱导 促纤维化表型。 (3) 确定 HIV 在共存环境中如何影响 M-MDSC 和 CD5L 功能 肝脏疾病。我们将通过单细胞转录组学/蛋白质组学对M-MDSCs和CD5L进行比较研究 肝脏 FNA 中包含 HIV、HIV/HCV、HIV/HBV 和 HIV/NASH 患者队列，我们​​将验证建议 使用共同暴露于这些损伤的原代/细胞系进行体外促纤维形成机制。这些研究一起 将极大地阐明单核细胞和巨噬细胞对艾滋病毒相关肝病的影响。

项目成果

Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis.

慢性病毒性肝炎治愈前后肝髓细胞室的单细胞图谱。

• DOI: 10.1016/j.jhep.2023.02.040
• 发表时间: 2023-03-01
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: Ang Cui;Bo Li;Michael S. Wallace;Anna L. K. Gonye;Chris Oetheimer;Hailey Patel;P. Tonnerre;J. Holmes;David J. Lieb;Brianna S. Yao;Aileen Ma;Kela Roberts;Marcos P S Damasio;Jonathan H. Chen;Daphnee Piou;C. Carlton;Joelle Brown;R. Mylvaganam;Jeremy Man Hon Fung;Moshe Sade;Jasneet Aneja;J. Gustafson;Eliana T. Epstein;Shadi Salloum;Cynthia Brisac;Ashraf Thabet;A. Kim;G. Lauer;N. Hacohen;R. Chung;N. Alatrakchi
• 通讯作者: N. Alatrakchi