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A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage.

ABSTRACT: Background & Aims:C-C motif chemokine ligand 24 (CCL24) is a chemokine that regulates inflammatory and fibrotic activities through its receptor, C-C motif chemokine receptor (CCR3). The aim of the study was to evaluate the involvement of the CCL24-CCR3 axis in liver fibrosis and inflammation and to assess the potential of its blockade, by a monoclonal anti-CCL24 antibody, as a therapeutic strategy for non-alcoholic steatohepatitis (NASH) and liver fibrosis. Methods:Expression of CCL24 and CCR3 was evaluated in liver biopsies and blood samples. CCL24 involvement in NAFLD/NASH pathogenesis was assessed in Ccl24 knockout mouse using the methionine-choline deficient (MCD) diet experimental model. Antifibrotic and anti-inflammatory effects of CM-101 were tested in the MCD and STAM mouse models and in the thioacetamide (TAA) model in rats. Liver enzymes, liver morphology, histology and collagen deposition, as well as fibrosis- and inflammation-related protein expression were assessed. Activation of hepatic stellate cells (HSCs) was evaluated in the human LX2 cell line. Results:Patients with NASH and advanced NAFLD exhibited significant expression of both CCL24 and CCR3 in liver and blood samples. In the experimental MCD-diet model, Ccl24 knockout mice showed an attenuated liver damage response compared to wild-type mice, exhibiting reduced histological NAFLD activity scores and fibrosis, as well as lower levels of liver enzymes. Blocking CCL24 using CM-101 robustly reduced liver damage in 3 experimental animal models (MCD, STAM and TAA), as demonstrated by attenuation of liver fibrosis and NAFLD activity score. Furthermore, blocking CCL24 by CM-101 significantly inhibited CCL24-induced HSC motility, ?-SMA expression and pro-collagen I secretion. Conclusion:Our results reveal that blocking CCL24 significantly attenuates liver fibrosis and inflammation and may have a potential therapeutic effect in patients with NASH and/or liver fibrosis. Lay summary:CCL24 is a chemokine that regulates inflammation and fibrosis. It was found to be significantly expressed in patients with non-alcoholic steatohepatitis, in whom it regulates profibrotic processes in the liver. Herein, we show that blockade of CCL24 using a monoclonal antibody robustly attenuated liver fibrosis and inflammation in animal models, thus suggesting a potential therapeutic role for an anti-CCL24 agent.

SUBMITTER: Segal-Salto M

PROVIDER: S-EPMC7005554 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage.

Segal-Salto Michal M Barashi Neta N Katav Avi A Edelshtein Vicktoria V Aharon Arnon A Hashmueli Sharon S George Jacob J Maor Yaakov Y Pinzani Massimo M Haberman Dan D Hall Andrew A Friedman Scott S Mor Adi A

JHEP reports : innovation in hepatology 20200102 1

<h4>Background & aims</h4>C-C motif chemokine ligand 24 (CCL24) is a chemokine that regulates inflammatory and fibrotic activities through its receptor, C-C motif chemokine receptor (CCR3). The aim of the study was to evaluate the involvement of the CCL24-CCR3 axis in liver fibrosis and inflammation and to assess the potential of its blockade, by a monoclonal anti-CCL24 antibody, as a therapeutic strategy for non-alcoholic steatohepatitis (NASH) and liver fibrosis.<h4>Methods</h4>Expression of C ...[more]

PMID: 32039405

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A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage.

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A blocking monoclonal antibody to CCL24 alleviates liver fibrosis and inflammation in experimental models of liver damage.

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