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: allergic rhinitis (AR), inflammation, C-C chemokine receptor type 1 antagonist, cytokines, chemokines


中文翻译：

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CC 趋化因子受体 1 型 (CCR1) 拮抗剂 BX471 对过敏性鼻炎的治疗作用。

目的和设计：过敏性鼻炎 (AR) 是一种免疫球蛋白 E (IgE) 介导的炎症性呼吸超敏反应，其特征是 Th2 细胞因子升高和炎症细胞浸润到鼻组织。BX471 是一种小分子 CC 趋化因子受体 1 型 (CCR1) 拮抗剂，通过阻断主要配体参与抑制炎症。在这项研究中，我们检测了 BX471 对卵白蛋白 (OVA) 诱导的 AR 小鼠模型的抗炎作用。
材料和方法：通过酶联免疫吸附试验 (ELISA) 测定 OVA 特异性 IgE 和 Th1 细胞因子的水平。通过实时聚合酶链反应 (RT-qPCR) 评估促炎介质的鼻腔表达。鼻腔切片用苏木精和伊红 (HE) 和高碘酸-希夫 (PAS) 染色以研究嗜酸性粒细胞浸润和杯状细胞化生。通过蛋白质印迹评估活化 B 细胞 (NF-kB)、Toll 样受体 4 (TLR4) 和 Toll 样受体 2 (TLR2) 的核因子 kappa-轻链增强子的相对蛋白质水平。通过流式细胞术测量CD4 ⁺ CD25 ⁺ Foxp3 ⁺ T 调节细胞 (Treg)的百分比。
结果：用 BX471 治疗的小鼠的打喷嚏和揉鼻行为显着减轻。BX471显着下调鼻腔促炎因子的表达，抑制肿瘤坏死因子α（TNF-α）和NF-kB的蛋白水平。CCR1 配体的阻断抑制了鼻腔中嗜酸性粒细胞的募集。此外，Treg 细胞群在 BX471 处理的小鼠中上调。
结论：BX471 通过抑制 CCR1 介导的 TNF-α 产生在 AR 小鼠模型中发挥抗炎作用，随后抑制炎症细胞中的 NF-kB 活化，导致 Th2 细胞因子、IL-1β、VCAM-1、GM 减少-CSF、RANTES 和 MIP-1α 表达水平，从而抑制嗜酸性粒细胞向鼻粘膜募集。此外，BX-471 通过增加 Treg 细胞数量表现出抗过敏​​作用。总体而言，BX471 代表了一种有前途的 AR 治疗策略。

关键词：变应性鼻炎（AR），炎症，CC趋化因子受体1型拮抗剂，细胞因子，趋化因子