CCL24 Regulates Biliary Inflammation and Fibrosis in Primary Sclerosing Cholangitis

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2023 Jun 22

PMID 37345655

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

Affiliations

Soon will be listed here.

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.

Citing Articles

CCL24 and Fibrosis: A Narrative Review of Existing Evidence and Mechanisms.

Greenman R, Weston C Cells. 2025; 14(2).

PMID: 39851534 PMC: 11763828. DOI: 10.3390/cells14020105.

Molecular Mechanisms of Fibrosis in Cholestatic Liver Diseases and Regenerative Medicine-Based Therapies.

Wang W, Lian H, Liang Y, Ye Y, Tam P, Chen Y Cells. 2024; 13(23).

PMID: 39682745 PMC: 11640075. DOI: 10.3390/cells13231997.

Portal Fibrosis and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease and Translational Opportunities.

Gupta V, Sehrawat T, Pinzani M, Strazzabosco M Gastroenterology. 2024; .

PMID: 39251168 PMC: 11885590. DOI: 10.1053/j.gastro.2024.07.044.

Long-Term Dietary Consumption of Grapes Affects Kidney Health in C57BL/6J Mice.

Dave A, Park E, Kofsky P, Dufresne A, Chakraborty S, Pezzuto J Nutrients. 2024; 16(14).

PMID: 39064752 PMC: 11280382. DOI: 10.3390/nu16142309.

Machine Learning Identifies Key Proteins in Primary Sclerosing Cholangitis Progression and Links High CCL24 to Cirrhosis.

Snir T, Greenman R, Aricha R, Frankel M, Lawler J, Saffioti F Int J Mol Sci. 2024; 25(11).

PMID: 38892228 PMC: 11173115. DOI: 10.3390/ijms25116042.

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