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Background: Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by inflammation, vasculopathy, and fibrosis affecting the skin and internal organs. Despite advancements in understanding the pathogenesis and treatment of SSc, there is still a lack of established effective therapies for SSc-induced fibrosis. CXCR7, a typical chemokine receptor (ACKR3), is known to play a role in various diseases, including fibrosis, cancer, coronary artery disease, and inflammatory diseases. This study aims to investigate the relationship between CXCR7 and SSc. Given the insufficient exploration of CXCR7's role in systemic sclerosis, additional research is warranted. Objectives: Various animal models replicate specific aspects of systemic sclerosis (SSc). Our choice for this study is the experimental mouse model of bleomycin-induced skin fibrosis, commonly employed to investigate SSc-related pathogenesis. We identified a selective CXCR7 modulator and assessed its anti-fibrotic effects in other fibrotic diseases. This research aims to determine the therapeutic impact of our novel compound, a CXCR7 modulator, on bleomycin-induced skin fibrosis in a mouse model. Methods: Female C57BL/6 mice received subcutaneous injections of Bleomycin hydrochloride at a dose of 50 µg/mouse, in a volume of 50 µL every other day (Day 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26). The injection sites were situated at the corners of a 1.5 x 1.5 cm square shaved area. IL1512 was administered orally at doses of 30 and 60 mg/kg, po, while Imatinib was administered intraperitoneally at a dose of 50 mg/kg for 28 days. Following the conclusion of the dosing period, all animals were sacrificed, and pre-shaved skin samples were collected. Skin fibrosis was assessed through measurements of skin collagen content and staining with Hematoxylin/Eosin (HE) and Masson's trichrome. Results: In the disease control group, dermal thickness and the area stained with Masson's trichrome were significantly increased compared to the normal control group. However, treatment with IL1512 (30 and 60 mg/kg, po) and Imatinib (50 mg/kg, ip) mitigated the increase in skin thickness. Similarly, the area stained with Masson's trichrome in the IL1512 and Imatinib groups was reduced compared to the bleomycin-treated disease group. Moreover, the administration of IL1512 resulted in a notable, dose-dependent decrease in skin fibrosis compared to the disease control group. Conclusion: IL1512 demonstrated a potent efficacy equal to or greater than Imatinib in bleomycin-induced skin fibrosis mouse model. We propose that IL1512 as the first CXCR7 modulator may have therapeutic potential in Systemic sclerosis disease. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.
Kim et al. (Sat,) studied this question.