Journal of Inflammation Research (Jul 2020)
Therapeutic Effect of C-C Chemokine Receptor Type 1 (CCR1) Antagonist BX471 on Allergic Rhinitis
Abstract
Suoyi Feng,1,2 Longzhu Ju,1 Ziqi Shao,1,3 Mark Grzanna,2 Lu Jia,4 Ming Liu5 1College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province 150030, People’s Republic of China; 2Science Department, The John Carroll School, Bel Air, Maryland, USA; 3College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei Province 430070, People’s Republic of China; 4School of Basic Medical Science, Shanxi University of Traditional Chinese Medicine, Jinzhong, Shanxi Province 030619, People’s Republic of China; 5State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang Province 150069, People’s Republic of ChinaCorrespondence: Suoyi FengScience Department, The John Carroll School, 703 E Churchville Road, Bel Air, Maryland 21014, USAEmail [email protected] LiuState Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, 678 Haping Road, Harbin, Heilongjiang Province 150069, People’s Republic of ChinaEmail [email protected] and Design: Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated inflammatory respiratory hypersensitivity characterized by elevated Th2 cytokines and infiltration of inflammatory cells to nasal tissues. BX471 is a small-molecule C-C chemokine receptor type 1 (CCR1) antagonist involved in suppression of inflammation via blocking of primary ligands. In this study, we examined the anti-inflammatory effect of BX471 on ovalbumin (OVA)-induced AR mice model.Materials and Methods: Levels of OVA-specific IgE and Th1 cytokines were determined by enzyme-linked immunosorbent assay (ELISA). Nasal expression of proinflammatory mediators was assessed by real-time polymerase chain reaction (RT-qPCR). Nasal-cavity sections were stained with hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) to study eosinophil infiltration and goblet cell metaplasia. Relative protein levels of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB), Toll-like Receptor 4 (TLR4) and Toll-like-receptor 2 (TLR2) were assessed by Western Blot. Percentage of CD4+CD25+Foxp3+ T regulatory cells (Treg) was measured by flow cytometry.Results: Mice treated with BX471 showed significantly relieved sneezing and nasal-rubbing behaviors. The expression of nasal proinflammatory factors was significantly downregulated by BX471, and protein levels of tumor necrosis factor alpha (TNF- α) and NF-kB were suppressed. Blockade of CCR1 ligands inhibited eosinophil recruitment in nasal cavity. In addition, Treg cells population were upregulated in BX471-treated mice.Conclusion: BX471 exerts anti-inflammatory effects in a mouse model of AR by inhibiting CCR1-mediated TNF-α production, which subsequently suppresses NF-kB activation in inflammatory cells, leading to a decrease in Th2 cytokines, IL-1β, VCAM-1, GM-CSF, RANTES, and MIP-1α expression levels, thus inhibiting eosinophil recruitment to nasal mucosa. In addition, BX-471 exhibits anti-allergic effect by increasing Treg cell population. Overall, BX471 represents a promising therapeutic strategy against AR.Keywords: allergic rhinitis (AR), inflammation, C-C chemokine receptor type 1 antagonist, cytokines, chemokines
