Ccl24, also known as eotaxin-2, is a pro-fibrotic and pro-inflammatory chemokine secreted by immune and epithelial cells. It promotes the trafficking of immune cells and activates pro-fibrotic cells through binding to the CCR3 receptor. Ccl24 is involved in various biological processes such as inflammation, fibrosis, and angiogenesis, and is associated with multiple fibro-inflammatory diseases [2,4].

In primary sclerosing cholangitis (PSC), neutralizing Ccl24 with the monoclonal antibody CM-101 in Mdr2-/-mice (a PSC model) significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Ccl24 neutralization also reduced proliferation and senescence of cholangiocytes. In addition, Ccl24 expression was elevated in primary human cholangiocytes and macrophages under pro-fibrotic conditions, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated by Ccl24 inhibition [1].

In systemic sclerosis (SSc), higher levels of Ccl24 and CCR3 were found in the skin and sera of patients compared with healthy controls, and elevated levels were associated with fibrosis and greater lung function deterioration. Growing evidence supports the anti-inflammatory and anti-fibrotic potential of a Ccl24-blocking antibody in preclinical models of SSc [2].

In skin fibrosis, increased matrix stiffness promotes skin fibrosis through the Piezo1-Wnt2/Wnt11-Ccl24 pathway, and Piezo1 knockdown in mice ameliorated skin fibrosis progression [3].

In heart failure, treatment with a Ccl24 antibody hindered Ang II-induced cardiac adverse remodeling by preventing cardiac hypertrophy and fibrosis, and decreased M2 macrophage and monocyte polarization [5].

In a mouse model of cholestasis, treatment with CM-101 effectively inhibited the accumulation of peribiliary neutrophils and macrophages, reducing biliary hyperplasia and fibrosis [6].

In conclusion, Ccl24 plays a crucial role in promoting inflammation and fibrosis in various disease conditions such as PSC, SSc, skin fibrosis, and heart failure. Gene-knockout (KO) or conditional-knockout (CKO) mouse models, along with in-vitro cell studies, have been instrumental in revealing the functions of Ccl24 in these diseases. These findings suggest that targeting Ccl24 could be a potential therapeutic strategy for treating fibro-inflammatory diseases [1,2,3,5,6].

References:

1. Greenman, Raanan, Segal-Salto, Michal, Barashi, Neta, Peled, Amnon, Mor, Adi. 2023. CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis. In JCI insight, 8, . doi:10.1172/jci.insight.162270. https://pubmed.ncbi.nlm.nih.gov/37345655/

2. Levy, Hilit, Gluschnaider, Udi, Balbir-Gurman, Alexandra. 2023. The Role of CCL24 in Systemic Sclerosis. In Rambam Maimonides medical journal, 14, . doi:10.5041/RMMJ.10504. https://pubmed.ncbi.nlm.nih.gov/37555717/

3. He, Jiahao, Cheng, Xinwei, Fang, Bin, Shan, Shengzhou, Li, Qingfeng. 2024. Mechanical stiffness promotes skin fibrosis via Piezo1-Wnt2/Wnt11-CCL24 positive feedback loop. In Cell death & disease, 15, 84. doi:10.1038/s41419-024-06466-3. https://pubmed.ncbi.nlm.nih.gov/38267432/

4. Greenman, Raanan, Weston, Chris J. 2025. CCL24 and Fibrosis: A Narrative Review of Existing Evidence and Mechanisms. In Cells, 14, . doi:10.3390/cells14020105. https://pubmed.ncbi.nlm.nih.gov/39851534/

5. Wang, Zhen, Xu, Hongfei, Chen, Miao, Zheng, Liangrong, Ma, Liang. 2022. CCL24/CCR3 axis plays a central role in angiotensin II-induced heart failure by stimulating M2 macrophage polarization and fibroblast activation. In Cell biology and toxicology, 39, 1413-1431. doi:10.1007/s10565-022-09767-5. https://pubmed.ncbi.nlm.nih.gov/36131165/

6. Greenman, Raanan, Snir, Tom, Katav, Avi, Mor, Adi, Vaknin, Ilan. 2024. The Role of CCL24 in Primary Sclerosing Cholangitis: Bridging Patient Serum Proteomics to Preclinical Data. In Cells, 13, . doi:10.3390/cells13030209. https://pubmed.ncbi.nlm.nih.gov/38334601/