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

Abstract

Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/ERjzrETqVkE 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 CC 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.

Chemokine receptor 1 pathway mediagtes the progression of airway inflammation in a smoking-induced chronic obstructive pulmonary disease mouse model

“…Furthermore, pretreatment with the CCR1 antagonist BX471 led to results similar to shRNA-CCR1 lentiviral transfection. BX471 may inhibit the release of in ammatory factors and recruitment of in ammatory cells via the CCR1 pathway [19] . Thus, BX471 is a potential target for the treatment of chronic airway in ammation in COPD.…”

Comprehensive analysis reveals hub genes associated with immune cell infiltration in allergic rhinitis

“…CCR1 , encoding a member of the beta chemokine receptor family, plays an important role in the recruitment of effector immune cells to the site of inflammation 40,41 . In an AR mouse model, inhibiting the CCR1‐mediated TNF‐α production has been shown to inhibit the activation of NF‐kB in inflammatory cells, resulting in a decrease in Th2 cytokine expression, thus inhibiting the recruitment of eosinophils to the nasal mucosa 42 . CSF1R encodes a cytokine that controls the production, differentiation, and function of macrophages 43 .…”

“…40,41 In an AR mouse model, inhibiting the CCR1mediated TNF-α production has been shown to inhibit the activation of NF-kB in inflammatory cells, resulting in a decrease in Th2 cytokine expression, thus inhibiting the recruitment of eosinophils to the nasal mucosa. 42 CSF1R encodes a cytokine that controls the production, differentiation, and function of macrophages. 43 It has been proven…”

“… 40 , 41 In an AR mouse model, inhibiting the CCR1‐mediated TNF‐α production has been shown to inhibit the activation of NF‐kB in inflammatory cells, resulting in a decrease in Th2 cytokine expression, thus inhibiting the recruitment of eosinophils to the nasal mucosa. 42 CSF1R encodes a cytokine that controls the production, differentiation, and function of macrophages. 43 It has been proven that established chronic allergic inflammation and airway remodeling can be reversed by inhibiting the CSF1‐CSF1R pathway, 44 suggesting the therapeutic potential of CSF1R inhibitors in cancer, and inflammatory, autoimmune, bone diseases.…”

Novel Findings on CCR1 Receptor in CNS Disorders: A Pathogenic Marker Useful in Controlling Neuroimmune and Neuroinflammatory Mechanisms in Parkinson’s Disease

“…After the BX471 discovery, several preclinical studies were performed to evaluate its biological properties, highlighting that this chemical compound modulated inflammation and immune-cell infiltration in experimental mouse models of renal fibrosis [21], asthma [22], and allergic rhinitis [23].…”