William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
NHLI, Imperial College London, London, UK.
Nat Commun. 2022 Nov 17;13(1):7029. doi: 10.1038/s41467-022-34695-7.
Neutrophil diapedesis is an immediate step following infections and injury and is driven by complex interactions between leukocytes and various components of the blood vessel wall. Here, we show that perivascular mast cells (MC) are key regulators of neutrophil behaviour within the sub-endothelial space of inflamed venules. Using confocal intravital microscopy, we observe directed abluminal neutrophil motility along pericyte processes towards perivascular MCs, a response that created neutrophil extravasation hotspots. Conversely, MC-deficiency and pharmacological or genetic blockade of IL-17A leads to impaired neutrophil sub-endothelial migration and breaching of the pericyte layer. Mechanistically, identifying MCs as a significant cellular source of IL-17A, we establish that MC-derived IL-17A regulates the enrichment of key effector molecules ICAM-1 and CXCL1 in nearby pericytes. Collectively, we identify a novel MC-IL-17A-pericyte axis as modulator of the final steps of neutrophil diapedesis, with potential translational implications for inflammatory disorders driven by increased neutrophil diapedesis.
中性粒细胞穿出是感染和损伤后的直接步骤，是由白细胞与血管壁各种成分之间的复杂相互作用驱动的。在这里，我们表明，血管周肥大细胞（MC）是炎症性小静脉内皮下空间中性粒细胞行为的关键调节剂。使用共聚焦活体显微镜，我们观察到定向的向血管周 MC 的 abluminal 中性粒细胞运动，这一反应产生了中性粒细胞渗出热点。相反，MC 缺陷和 IL-17A 的药理学或基因阻断导致中性粒细胞向血管下迁移受损和周细胞层破裂。从机制上讲，我们确定 MC 是 IL-17A 的重要细胞来源，从而建立了 MC 衍生的 IL-17A 调节附近周细胞中关键效应分子 ICAM-1 和 CXCL1 的富集。总的来说，我们确定了一种新的 MC-IL-17A-周细胞轴作为中性粒细胞穿出的最后步骤的调节剂，对于由中性粒细胞穿出增加驱动的炎症性疾病具有潜在的转化意义。
