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CCL24 调节原发性硬化性胆管炎中的胆道炎症和纤维化。

CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis.

机构信息

Chemomab Therapeutics Ltd., Tel Aviv, Israel.

Gene Therapy Institute, Hadassah Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.

出版信息

JCI Insight. 2023 Jun 22;8(12):e162270. doi: 10.1172/jci.insight.162270.

DOI:10.1172/jci.insight.162270
PMID:37345655
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10371243/
Abstract

ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2-knockout (Mdr2-/-) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.

摘要

CCL24 是一种促纤维化、促炎的趋化因子，在几种慢性纤维化疾病中表达。在肝脏中，CCL24 参与纤维化和炎症反应，阻断 CCL24 可减少实验模型中的肝损伤。我们研究了 CCL24 在原发性硬化性胆管炎 (PSC) 中的作用，并评估了阻断 CCL24 在该疾病中的潜在治疗效果。多药耐药基因 2 敲除 (Mdr2-/-) 小鼠的肝脏巨噬细胞中表达 CCL24，可作为相关的实验性 PSC 模型。CCL24 中和单克隆抗体 CM-101 显著改善了胆管区的炎症、纤维化和胆汁淤积相关标志物。此外，通过空间转录组学，我们观察到 CCL24 中和后胆管细胞的增殖和衰老减少。接下来，我们证明 CCL24 在原代人胆管细胞和巨噬细胞的促纤维化条件下表达上调，并诱导原代人肝星状细胞和胆管细胞的增殖，CCL24 抑制后这种增殖被减弱。相应地，在 PSC 患者的肝活检中发现 CCL24 高度表达。CCL24 血清水平与增强的肝纤维化评分相关，尤其是在碱性磷酸酶水平较高的患者中。这些结果表明，通过减少肝脏炎症、纤维化和胆汁淤积，阻断 CCL24 可能对 PSC 患者具有治疗作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/9fdae54a41a1/jciinsight-8-162270-g027.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/bab34fcce936/jciinsight-8-162270-g020.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/c6de4eb24079/jciinsight-8-162270-g025.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/4ba0bd165bc3/jciinsight-8-162270-g026.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/9fdae54a41a1/jciinsight-8-162270-g027.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/bab34fcce936/jciinsight-8-162270-g020.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/dc091ce3683d/jciinsight-8-162270-g021.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/1a7249e3e5ab/jciinsight-8-162270-g022.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/49837ff22f9d/jciinsight-8-162270-g023.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/ef4331eb89b2/jciinsight-8-162270-g024.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/c6de4eb24079/jciinsight-8-162270-g025.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/4ba0bd165bc3/jciinsight-8-162270-g026.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56f9/10371243/9fdae54a41a1/jciinsight-8-162270-g027.jpg

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