Whether respiratory epithelial cells regulate the final transit of extravasated neutrophils into the inflamed airspace or are a passive barrier is poorly understood. Alveolar epithelial type 1 (AT1) cells, best known for solute transport and gas exchange, have few established immune roles. Epithelial membrane protein 2 (EMP2), a tetraspan protein that promotes recruitment of integrins to lipid rafts, is highly expressed in AT1 cells but has no known function in lung biology. Here, we show that Emp2^–/– mice exhibit reduced neutrophil influx into the airspace after a wide range of inhaled exposures. During bacterial pneumonia, Emp2^–/– mice had attenuated neutrophilic lung injury and improved survival. Bone marrow chimeras, intravital neutrophil labeling, and in vitro assays suggested that defective transepithelial migration of neutrophils into the alveolar lumen occurs in Emp2^–/– lungs. Emp2^–/– AT1 cells had dysregulated surface display of multiple adhesion molecules, associated with reduced raft abundance. Epithelial raft abundance was dependent upon putative cholesterol-binding motifs in EMP2, whereas EMP2 supported adhesion molecule display and neutrophil transmigration through suppression of caveolins. Taken together, we propose that EMP2-dependent membrane organization ensures proper display on AT1 cells of a suite of proteins required to instruct paracellular neutrophil traffic into the alveolus.

中文翻译：

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上皮膜蛋白2控制嗜中性粒细胞向上皮的跨上皮迁移

呼吸上皮细胞是调节外渗的中性粒细胞最终进入发炎空域的通道还是被动屏障，人们对此知之甚少。肺泡上皮1型（AT1）细胞以溶质运输和气体交换而闻名，几乎没有建立起免疫作用。上皮膜蛋白2（EMP2）是一种四跨膜蛋白，可促进整合素向脂质筏的募集，在AT1细胞中高度表达，但在肺生物学中没有已知的功能。在这里，我们显示了Emp2 ^-/-小鼠在大量吸入暴露后表现出减少的嗜中性白细胞流入空气空间。在细菌性肺炎期间，Emp2 ^{– / –}小鼠减轻了嗜中性肺损伤并提高了存活率。骨髓嵌合体，活体内嗜中性白细胞标记和体外测定表明，Emp2- ^{– / –}肺中嗜中性白细胞经上皮向肺泡腔的迁移不良。Emp2 ^{– / –}AT1细胞的多个粘附分子的表面显示失调，与筏丰度降低有关。上皮筏的丰度取决于EMP2中假定的胆固醇结合基序，而EMP2通过抑制小窝蛋白支持粘附分子展示和中性粒细胞迁移。两者合计，我们建议依赖EMP2的膜组织可确保在AT1细胞上正确显示指示细胞旁嗜中性粒细胞运输进入肺泡所需的一组蛋白质。