Airway epithelial cells (AECs) participate in allergic airway inflammation by producing mediators in response to allergen stimulation. Whether ovalbumin (OVA) challenge promotes exosome release from AECs (OVA-challenged AEC-derived exosomes (OAEs)), thereby affecting airway inflammation, as well as the underlying mechanisms, is unknown. Our study showed that AECs released an increased number of exosomes after OVA challenge, and the expression of Plexin B2 (PLXNB2; a natural CD100 ligand) was increased by a massive 85.7-fold in OAEs than in PBS-treated AEC-derived exosomes (PAEs). CD100⁺F4/80⁺ macrophages engulfed OAEs to trigger the transcription of pro-inflammatory chemokines and cytokines. Plxnb2 transcripts increased in asthmatic lungs, and similarly, PLXNB2 protein was highly enriched in exosomes purified from asthmatic bronchoalveolar lavage (BAL) fluid. Furthermore, aspiration of PLXNB2 or OAEs increased the recruitment of lung neutrophils, monocytes, eosinophils and dendritic cells in OVA-challenged mice. Mechanistically, OAE aspiration enhanced the cleavage of CD100 by MMP14, which manifested as an increase in the soluble CD100 (sCD100) level in BAL fluid and lung homogenates. Knockdown of Mmp14 in macrophages prevented the cleavage of CD100 and reduced Ccl2, Ccl5 and Cxcl2 transcription. These data indicate that PLXNB2-containing OAEs aggravate airway asthmatic inflammation via cleavage of CD100 by MMP14, suggesting potential therapeutic targets of OAE-mediated asthma exacerbations.

中文翻译：

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增加的气道上皮细胞衍生的外泌体通过 CD100 脱落激活巨噬细胞介导的过敏性炎症

气道上皮细胞 (AEC) 通过响应过敏原刺激产生介质参与过敏性气道炎症。卵白蛋白 (OVA) 挑战是否促进 AEC 的外泌体释放（OVA 挑战的 AEC 衍生的外泌体 (OAEs)），从而影响气道炎症，以及潜在的机制，尚不清楚。我们的研究表明，在 OVA 攻击后，AECs 释放的外泌体数量增加，并且 Plexin B2（PLXNB2；一种天然 CD100 配体）的表达在 OAEs 中比 PBS 处理的 AEC 衍生的外泌体（PAEs ）。CD100 ⁺ F4/80 ⁺巨噬细胞吞噬 OAE 以触发促炎趋化因子和细胞因子的转录。plxnb2哮喘肺中的转录物增加，同样，PLXNB2 蛋白在从哮喘支气管肺泡灌洗液 (BAL) 液中纯化的外泌体中高度富集。此外，PLXNB2 或 OAE 的抽吸增加了 OVA 攻击小鼠肺中性粒细胞、单核细胞、嗜酸性粒细胞和树突状细胞的募集。从机制上讲，OAE 抽吸增强了 MMP14 对 CD100 的裂解，这表现为 BAL 液和肺匀浆中可溶性 CD100 (sCD100) 水平的增加。巨噬细胞中Mmp14的敲低阻止了 CD100 的切割并减少了 Ccl2、Ccl5和Cxcl2转录。这些数据表明，含有 PLXNB2 的 OAE 通过 MMP14 裂解 CD100 加重气道哮喘炎症，表明 OAE 介导的哮喘恶化的潜在治疗靶点。