CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis
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
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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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 2

CM-101 (D8) abrogates macrophage accumulation and reduces ductular expansion in Mdr2–/– mice.

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CM-101 (D8) abrogates macrophage accumulation and reduces ductular expan...
(A) Immunohistochemistry staining of Iba1 in 3-month-old WT and Mdr2–/– mice. (B–E) Immunofluorescence staining of liver cholangiocytes and macrophages in CM-101–treated (10 mg/kg) or vehicle-treated Mdr2–/– mice. (B) Quantification of the injured peribiliary area, based on Iba1 and pan-CK staining (n = 50 fields, 5 mice in each group). (C) Representative Mdr2–/– liver sections stained against Iba1 for macrophages and pan-CK for cholangiocytes (×40 original magnification). (D and E) Quantification of Iba1 and pan-CK staining (n = 38–40 fields, 7 mice in each group). (F) Representative Mdr2–/– liver sections stained against Iba1 and CX3CR1 for recruited macrophages (×40 original magnification). (G and H) Quantification of recruited macrophages (Iba1-positive and CX3CR1-positive, G) and nonrecruited macrophages (Iba1-positive and CX3CR1-negative, H) (n = 30 fields, 5 mice in each group). Data are mean ± SEM. Mann-Whitney test, *P ≤ 0.05, ***P ≤ 0.001, ****P ≤ 0.0001.