CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis
Raanan Greenman, … , Amnon Peled, Adi Mor
Raanan Greenman, … , Amnon Peled, Adi Mor
Published June 22, 2023
Citation Information: JCI Insight. 2023;8(12):e162270. https://doi.org/10.1172/jci.insight.162270.
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Research Article Hepatology Inflammation

CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis

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.

Authors

Raanan Greenman, Michal Segal-Salto, Neta Barashi, Ophir Hay, Avi Katav, Omer Levi, Ilan Vaknin, Revital Aricha, Sarit Aharoni, Tom Snir, Inbal Mishalian, Devorah Olam, Johnny Amer, Ahmad Salhab, Rifaat Safadi, Yaakov Maor, Palak Trivedi, Christopher J. Weston, Francesca Saffioti, Andrew Hall, Massimo Pinzani, Douglas Thorburn, Amnon Peled, Adi Mor

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Figure 8

CCL24 and CCR3 are highly expressed in the bile duct areas and costained with inflammatory and fibrotic cellular markers in PSC patients’ liver biopsies.

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CCL24 and CCR3 are highly expressed in the bile duct areas and costained...
Sequential slides from bile ducts of patients with PSC and healthy controls were stained. (A) Representative images from healthy control and PSC patient livers stained for H&E, pan-CK, CCR3, CCL24, α-SMA, and Iba1. Staining demonstrates bile ducts surrounded by blood vessels, inflammatory cells, and activated fibroblasts. CCL24 expression is observed in cholangiocytes and in the inflammatory cells surrounding bile duct area. (B–D) High-magnification images of the biliary and peribiliary area show the colocalization of Iba1 and CCL24 (B), of α-SMA and CCR3 (C), and of pan-CK and CCL24 (D). Scale bar represents 50 μm. (E) ELF score and CCL24 levels in the serum of patients with PSC (n = 20) were measured for each patient. Pearson’s correlation was used to identify association of CCL24 to fibrotic biomarkers and liver damage. Dividing this cohort by ALP levels associated with higher risk of progression (F), resulting in higher correlation of CCL24 and the fibrotic biomarker, ELF.