Key Points Eosinophilia is a characteristic feature of allergic airway inflammation and asthma. TrkA activation by eotaxin-1 promotes eosinophil migration and airway inflammation. Inhibiting TrkA kinase mitigates airway eosinophilia and suppresses a Th2 phenotype. Visual Abstract Eosinophilia is a hallmark of allergic airway inflammation (AAI). Identifying key molecules and specific signaling pathways that regulate eosinophilic inflammation is critical for development of novel therapeutics. Tropomycin receptor kinase A (TrkA) is the high-affinity receptor for nerve growth factor. AAI is associated with increased expression of TrkA by eosinophils; however, the functional role of TrkA in regulating eosinophil recruitment and contributing to AAI is poorly understood. This study identifies, to our knowledge, a novel mechanism of eotaxin-mediated activation of TrkA and its role in regulating eosinophil recruitment by using a chemical-genetic approach to specifically inhibit TrkA kinase activity with 1-NM-PP1 in TrkAF592A–knock-in (TrkA-KI) eosinophils. Blockade of TrkA by 1-NM-PP1 enhanced eosinophil spreading on VCAM-1 but inhibited eotaxin-1 (CCL11)–mediated eosinophil migration, calcium flux, cell polarization, and ERK1/2 activation, suggesting that TrkA is an important player in the signaling pathway activated by eotaxin-1 during eosinophil migration. Further, blockade of matrix metalloprotease with BB-94 inhibited eotaxin-1–induced TrkA activation and eosinophil migration, additively with 1-NM-PP1, indicating a role for matrix metalloproteases in TrkA activation. TrkA inhibition in Alternaria alternata–challenged TrkA-KI mice markedly inhibited eosinophilia and attenuated various features of AAI. These findings are indicative of a distinctive eotaxin-mediated TrkA-dependent signaling pathway, which, in addition to other TrkA-activating mediators, contributes to eosinophil recruitment during AAI and suggests that targeting the TrkA signaling pathway to inhibit eosinophil recruitment may serve as a therapeutic strategy for management of eosinophilic inflammation in allergic airway disease, including asthma.

中文翻译：

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原肌球蛋白受体激酶 A 对嗜酸性粒细胞募集和过敏性气道炎症的调节


要点 嗜酸性粒细胞增多是过敏性气道炎症和哮喘的一个特征。 eotaxin-1 激活 TrkA 可促进嗜酸性粒细胞迁移和气道炎症。抑制 TrkA 激酶可减轻气道嗜酸性粒细胞增多并抑制 Th2 表型。视觉摘要 嗜酸性粒细胞增多是过敏性气道炎症 (AAI) 的一个标志。识别调节嗜酸性粒细胞炎症的关键分子和特定信号通路对于开发新疗法至关重要。原霉素受体激酶 A (TrkA) 是神经生长因子的高亲和力受体。 AAI 与嗜酸性粒细胞 TrkA 表达增加有关；然而，人们对 TrkA 在调节嗜酸性粒细胞募集和促进 AAI 方面的功能作用知之甚少。据我们所知，这项研究确定了嗜酸性粒细胞活化趋化因子介导的 TrkA 激活的新机制及其在调节嗜酸性粒细胞募集中的作用，通过使用化学遗传学方法在 TrkAF592A–knock-in 中使用 1-NM-PP1 特异性抑制 TrkA 激酶活性(TrkA-KI) 嗜酸性粒细胞。 1-NM-PP1 阻断 TrkA 增强了 VCAM-1 上的嗜酸性粒细胞扩散，但抑制了嗜酸性粒细胞趋化因子-1 (CCL11) 介导的嗜酸性粒细胞迁移、钙流、细胞极化和 ERK1/2 激活，表明 TrkA 在嗜酸性粒细胞迁移过程中由eotaxin-1激活的信号通路。此外，用 BB-94 阻断基质金属蛋白酶可抑制 eotaxin-1 诱导的 TrkA 激活和嗜酸性粒细胞迁移，再加上 1-NM-PP1，表明基质金属蛋白酶在 TrkA 激活中的作用。在链格孢感染的 TrkA-KI 小鼠中，TrkA 抑制显着抑制嗜酸性粒细胞增多并减弱 AAI 的各种特征。 这些发现表明了独特的嗜酸性粒细胞趋化因子介导的 TrkA 依赖性信号通路，除了其他 TrkA 激活介质之外，该通路还有助于 AAI 期间嗜酸性粒细胞的募集，并表明靶向 TrkA 信号通路抑制嗜酸性粒细胞募集可能作为一种治疗方法。治疗过敏性气道疾病（包括哮喘）中嗜酸性粒细胞炎症的策略。