Therapeutic Effect of C-C Chemokine Receptor Type 1 (CCR1) Antagonist BX471 on Allergic Rhinitis

  • J Inflamm Res. 2020 Jul 21;13:343-356. doi: 10.2147/JIR.S254717.
Suoyi Feng  1  2 ,  Longzhu Ju  1 ,  Ziqi Shao  1  3 ,  Mark Grzanna  2 ,  Lu Jia  4 ,  Ming Liu  5
Affiliations
  • 1. College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province 150030, People's Republic of China.
  • 2. Science Department, The John Carroll School, Bel Air, Maryland, USA.
  • 3. College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei Province 430070, People's Republic of China.
  • 4. School of Basic Medical Science, Shanxi University of Traditional Chinese Medicine, Jinzhong, Shanxi Province 030619, People's Republic of China.
  • 5. State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang Province 150069, People's Republic of China.
PMID: 32801828 DOI: 10.2147/JIR.S254717
Abstract

Objective 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
C-C chemokine receptor type 1 antagonist; allergic rhinitis (AR); chemokines; cytokines; inflammation.
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