Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Front Immunol. 2024 Oct 17;15:1470016. doi: 10.3389/fimmu.2024.1470016. eCollection 2024.
Allergic asthma has been linked to the activation of mast cells (MCs) by the neuropeptide substance P (SP), but the mechanism underlying this neuroimmune interaction is unknown. Substance P produced from cutaneous nociceptors activates MCs via Mas-related G-protein-coupled receptor B2 (MrgprB2) to enhance type 2 immune response in experimental atopic dermatitis in mice. We recently showed that the adapter protein β-arrestin2 (β-arr2) contributes to MrgprB2-mediated MC chemotaxis. The goals of this study were to determine if MrgprB2 facilitates neuroimmune interaction in IgE (FcεRI)-mediated allergic airway inflammation (AAI) and to assess if this response is modulated by β-arr2.
Wild-type (WT), mice and mice with MC-specific deletion of β-arr2 ( / ) were passively sensitized with anti-TNP-IgE and challenged with antigen. The generation of SP and MC recruitment in the lung were determined by immunofluorescence and toluidine blue staining, respectively. The transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokines in lung tissue were assessed by RT-PCR, and the release of selected cytokines in bronchoalveolar lavage (BAL) was determined by ELISA. Eosinophil and neutrophil recruitment in lung tissue and BAL were determined by immunofluorescence staining and flow cytometry, respectively. Goblet cell hyperplasia was determined by periodic acid-Schiff staining.
Following IgE sensitization and antigen challenge in WT mice, SP generation, and MC recruitment, transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokine were upregulated when compared to the control challenge. TNF-α, Th2 cytokine production, eosinophil/neutrophil recruitment, and goblet cell hyperplasia were also increased. These responses were significantly reduced in and / mice.
The data presented herein suggest that SP-mediated MrgprB2 activation contributes to AAI and goblet cell hyperplasia in mice. Furthermore, these responses are modulated by β-arr2, which promotes MC recruitment to facilitate their activation through FcεRI.
神经肽 P 物质（SP）可激活肥大细胞（MC），导致变应性哮喘，但其神经免疫相互作用的机制尚不清楚。皮肤伤害感受器产生的 P 物质通过与 Mas 相关 G 蛋白偶联受体 B2（MrgprB2）结合，激活 MC，增强实验性变应性皮炎小鼠的 2 型免疫反应。我们最近发现衔接蛋白β-arrestin2（β-arr2）有助于 MrgprB2 介导的 MC 趋化作用。本研究旨在确定 MrgprB2 是否有助于 IgE（FcεRI）介导的变应性气道炎症（AAI）中的神经免疫相互作用，并评估该反应是否受 β-arr2 调节。
野生型（WT）、 和 MC 特异性缺失β-arr2 的 / 小鼠通过抗 TNP-IgE 被动致敏，并接受抗原挑战。通过免疫荧光和甲苯胺蓝染色分别确定 SP 的产生和 MC 在肺中的募集情况。通过 RT-PCR 评估肺组织中 Tac1、MrgprB2、TNF-α 和 Th2 细胞因子的转录，通过 ELISA 测定支气管肺泡灌洗液（BAL）中选定细胞因子的释放。通过免疫荧光染色和流式细胞术分别测定肺组织和 BAL 中的嗜酸性粒细胞和中性粒细胞募集情况，通过过碘酸-Schiff 染色测定杯状细胞增生。
在 WT 小鼠 IgE 致敏和抗原攻击后，与对照挑战相比，SP 的产生和 MC 的募集，Tac1、MrgprB2、TNF-α 和 Th2 细胞因子的转录均上调。TNF-α、Th2 细胞因子产生、嗜酸性粒细胞/中性粒细胞募集和杯状细胞增生也增加。这些反应在 和 / 小鼠中显著降低。
本文提供的资料表明，SP 介导的 MrgprB2 激活有助于小鼠的 AAI 和杯状细胞增生。此外，这些反应受 β-arr2 调节，β-arr2 通过 FcεRI 促进 MC 募集，从而促进其激活。
