R243 is a CCR8 receptor inhibitor that suppresses the signaling pathways triggered by CCL1, the endogenous ligand of CCR8[1-2]. R243 is primarily utilized in research related to immune and inflammatory diseases[3].
In vitro, treatment of mouse RAW264.7 macrophages and bone marrow-derived macrophages (BMDMs) with R243 (10µM) for 24 hours significantly inhibited CCL1-driven chemotactic migration in a CCL1-induced (10ng/mL) Transwell migration assay, although the inhibitory effect on the migration of human THP-1 monocytes was not significant [4]. When mouse peritoneal macrophages (PMφ) stimulated with LPS (100ng/mL) were treated with R243 (0–10µM) for 24 hours, R243 significantly suppressed the secretion of TNF-α, IL-6, and IL-10, and reduced the phosphorylation levels of the JNK and NF-κB signaling pathways[5].
In vivo, a peritoneal fibrosis mouse model, R243 (1.0mg/kg; administered via intraperitoneal injection three times a week for 28 days) significantly alleviated chlorhexidine gluconate-induced peritoneal inflammation and fibrosis by functionally inhibiting the CCR8 receptor. This was evidenced by reduced peritoneal thickness, decreased collagen deposition, and diminished macrophage infiltration[6]. In a thermal hyperalgesia test model, R243 (0.3–1mg/kg; administered via intraperitoneal injection 30 minutes prior to CCL1) dose-dependently inhibited CCL1 (10µg/kg)-induced systemic thermal analgesia[7].
References:
[1] Berenguer J, Lagerweij T, Zhao XW, et al. Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8. J Extracell Vesicles. 2018 Mar 13;7(1):1446660.
[2] García-Domínguez M, González-Rodríguez S, Hidalgo A, et al. Kappa-opioid receptor-mediated thermal analgesia evoked by the intrathecal administration of the chemokine CCL1 in mice. Fundam Clin Pharmacol. 2021 Dec;35(6):1109-1118.
[3] Ding H, Xu X, Zhu Y, et al. Inhibition of Alkbh5 Attenuates Lipopolysaccharide-Induced Lung Injury by Promoting Ccl1 m6A and Treg Recruitment. Cell Prolif. 2025 Sep;58(9):e70032.
[4] Geervliet E, Arora S, Donohue D, et al. Design, molecular characterization and therapeutic investigation of a novel CCR8 peptide antagonist that attenuates acute liver injury by inhibiting infiltration and activation of macrophages. Acta Pharm Sin B. 2025 Apr;15(4):2114-2133.
[5] Oshio T, Kawashima R, Kawamura YI, et al. Chemokine receptor CCR8 is required for lipopolysaccharide-triggered cytokine production in mouse peritoneal macrophages. PLoS One. 2014 Apr 8;9(4):e94445.
[6] Lee Y, Lee J, Park M, et al. Inflammatory chemokine (C-C motif) ligand 8 inhibition ameliorates peritoneal fibrosis. FASEB J. 2023 Jan;37(1):e22632.
[7] García-Domínguez M, Aguirre A, Lastra A, et al. The Systemic Administration of the Chemokine CCL1 Evokes Thermal Analgesia in Mice Through the Activation of the Endocannabinoid System. Cell Mol Neurobiol. 2019 Nov;39(8):1115-1124.