Immune Modulation of Macrophages in Obstructive Cholestasis

巨噬细胞在阻塞性胆汁淤积中的免疫调节

• 批准号: 10176405
• 负责人: Joshua Brian Wechsler
• 金额: $ 19.27万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176405
• 关键词: Adult; Agonist; Anti-Inflammatory Agents; Bile Acids; Bile fluid; Biliary; Biliary Atresia; Biological Markers; Bone Marrow; C57BL/6 Mouse; Cells; Characteristics; Child; Childhood; Cholestasis; Clinical; Clinical Research; Computational Biology; Data; Data Discovery; Data Set; Disease; Disease Progression; Ensure; Etiology; Evaluation; Foundations; Future; Genetic Transcription; Hepatic; Heterogeneity; Hour; Human; Immune; Immune response; Immune system; Immunology; Immunomodulators; Immunotherapy; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Laboratories; Laboratory Markers; Leukocytes; Ligation; Liver; Liver diseases; Medical; Modeling; Mus; Myeloid Cells; Obstruction; Operative Surgical Procedures; Orphan; PTPRC gene; Pathogenesis; Patients; Physiology; Play; Population; Primary biliary cirrhosis; Prognosis; RORA gene; Recovery; Research; Retinoic Acid Receptor; Role; Sampling; Sampling Studies; System; Therapeutic; Therapeutic Trials; Tissues; Translating; Transplantation; United States; analog; bile acid metabolism; bile duct; cholestatic injury; cholestatic liver disease; disease phenotype; experimental study; human disease; immunomodulatory therapies; immunoregulation; innovation; liver injury; liver transplantation; macrophage; mouse model; new therapeutic target; non-alcoholic; nonalcoholic steatohepatitis; novel; patient population; predicting response; prevent; primary sclerosing cholangitis; receptor; repaired; response; restoration; retinoic acid receptor alpha; single-cell RNA sequencing; tissue injury; treatment strategy

PROJECT SUMMARY: Obstructive cholestatic liver diseases carry a high medical burden as there is no medical therapy to prevent disease progression and thus they remain a leading indication for liver transplantation. While the initial target in obstructive cholangiopathies is the bile duct, the immune response is the major cause for ongoing liver injury. Macrophages are known to play a significant role in the mechanism of cholestatic liver injury, however, disease- modulating immunotherapies have not been established and represent an unmet medical need. We have been the first to perform single-cell RNA sequencing (scRNA-seq) on cholestatic liver samples and will use this preliminary data in the current study to overcome the gap in medical therapy. We have identified a subset of RORA-expressing macrophages in cholestatic liver samples that is at the interface between cholestatic and normal macrophages on pseudotime trajectory analysis. RORA encodes a retinoic acid receptor-related orphan receptor alpha (ROR) that is known to promote anti-inflammatory polarization of human macrophages. Our data suggests that RORA+ macrophages may emerge in cholestatic liver injury and thus be a novel therapeutic target. While ROR-agonism has shown improvement in hepatic injury in a murine model of non-alcoholic steatohepatitis, the role of RORA in cholestatic liver disease has not been investigated. We hypothesize that RORA+ hepatic macrophages are necessary for the reparative response after cholestatic injury; thus, ROR agonism will promote repair through the conversion of pro-inflammatory macrophages into this critical pro-restorative subset. We will investigate our hypothesis through: 1) correlation between clinical parameters of liver injury and the transcriptional prolife of RORA+ hepatic macrophages in cholestatic and non-cholestatic human liver diseases using scRNA-seq, 2) identification of the reparative macrophage immune response after alleviation of biliary obstruction using an innovative murine model of reversible bile duct ligation, and 3) evaluation of changes in disease phenotype in our murine model upon ROR-agonism. Transcriptional correlation between human and murine macrophage subsets will provide the foundation to translate findings from the current study into future human immune-modulatory therapeutic trials. In addition, data obtained from this proposal will enable further studies on ROR-agonism in disease-specific murine models of cholestasis as well as fate-mapping experiments to determine the origin (bone-marrow derived versus tissue-resident) of the ROR-responsive macrophages.

项目概要： 阻塞性胆汁淤积性肝病带来沉重的医疗负担，因为没有药物治疗可以预防 疾病进展，因此它们仍然是肝移植的主要适应症。虽然最初的目标是在 阻塞性胆管病是胆管的免疫反应，是造成肝脏持续损伤的主要原因。 众所周知，巨噬细胞在胆汁淤积性肝损伤的机制中发挥着重要作用，然而，疾病- 调节免疫疗法尚未建立，并且代表着未满足的医疗需求。我们曾经 第一个对胆汁淤积性肝脏样本进行单细胞 RNA 测序 (scRNA-seq) 并将使用该技术 目前研究的初步数据弥补了药物治疗方面的差距。 我们已经在胆汁淤积性肝脏样本中鉴定出位于界面处的表达 RORA 的巨噬细胞子集 胆汁淤积和正常巨噬细胞之间的伪时间轨迹分析。 RORA 编码视黄酸 受体相关的孤儿受体α (RORα)，已知可促进人类抗炎极化 巨噬细胞。我们的数据表明 RORA+ 巨噬细胞可能出现在胆汁淤积性肝损伤中，因此 一个新的治疗靶点。 RORα 激动剂在小鼠模型中显示出可改善肝损伤 对于非酒精性脂肪性肝炎，RORA 在胆汁淤积性肝病中的作用尚未得到研究。我们 假设 RORA+ 肝巨噬细胞对于术后修复反应是必需的 胆汁淤积性损伤；因此，RORα激动剂将通过促炎细胞的转化来促进修复。 巨噬细胞进入这个关键的促恢复亚群。 我们将通过以下方式研究我们的假设：1）肝损伤的临床参数与肝损伤的临床参数之间的相关性。 RORA+肝巨噬细胞在胆汁淤积性和非胆汁淤积性人类肝脏疾病中的转录增殖 使用 scRNA-seq，2) 鉴定胆汁缓解后的修复性巨噬细胞免疫反应 使用可逆胆管结扎的创新小鼠模型进行梗阻，以及 3) 评估 RORα 激动小鼠模型中的疾病表型。人类和人类之间的转录相关性 小鼠巨噬细胞亚群将为将当前研究结果转化为未来奠定基础 人体免疫调节治疗试验。此外，从该提案中获得的数据将有助于进一步 疾病特异性胆汁淤积小鼠模型中 RORα 激动的研究以及命运图谱实验 确定 RORα 反应性巨噬细胞的起源（骨髓来源与组织驻留）。

项目成果

Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations.

• DOI: 10.1371/journal.pone.0244743
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Taylor SA;Chen SY;Gadhvi G;Feng L;Gromer KD;Abdala-Valencia H;Nam K;Dominguez ST;Montgomery AB;Reyfman PA;Ostilla L;Wechsler JB;Cuda CM;Green RM;Perlman H;Winter DR
• 通讯作者: Winter DR

Single-cell sequencing of a novel model of neonatal bile duct ligation in mice identifies macrophage heterogeneity in obstructive cholestasis.

小鼠新生儿胆管连接的新型模型的单细胞测序鉴定了阻塞性胆汁淤积中的巨噬细胞异质性。

• DOI: 10.1038/s41598-023-41207-0
• 发表时间: 2023-08-29
• 期刊: Scientific reports
• 影响因子: 4.6