Alpha-1 antitrypsin inhibits fractalkine-mediated monocyte-lung endothelial cell interactions.
Alpha-1 antitrypsin inhibits fractalkine-mediated monocyte-lung endothelial cell interactions.
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Alpha-1 抗胰蛋白酶抑制 fractalkine 介导的单核细胞-肺内皮细胞相互作用。
DOI：
10.1152/ajplung.00023.2023
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Serb
中科院分区：
文献类型：
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作者：
Mikosz,Andrew;Ni,Kevin;Gally,Fabienne;Pratte,KatherineA;Winfree,Seth;Lin,Qiong;Echelman,Isabelle;Wetmore,Brianna;Cao,Danting;Justice,MatthewJ;Sandhaus,RobertA;Maier,Lisa;Strange,Charlie;Bowler,RussellP;Petrache,Irina;Serb
慢性阻塞性肺疾病(COPD)的特征是内皮屏障的破裂和白细胞重新聚集到空气中而导致炎症无法消退。在控制白细胞募集的配体-受体轴中，全长的Fractalkine配体(CX3CL1)-受体(CX3CR1)确保了内皮细胞-白细胞的动态平衡相互作用。香烟烟雾暴露和呼吸道病原体增加内皮脱落酶的表达，如α-去整合素和金属蛋白酶结构域17(ADAM17，TACE)，该酶被抗蛋白酶α-1抗胰蛋白酶(AAT)抑制。在系统内皮细胞中，TACE裂解CX3CL1释放可溶性CX3CL1(SCX3CL1)。在CS暴露期间，AAT是否抑制sCX3CL1脱落和CX3CR1+白细胞跨肺微血管内皮细胞迁移尚不清楚。我们研究了sCX3CL1脱落的机制，它在内皮-单核细胞相互作用中的作用，以及AAT在急性炎症过程中对这些相互作用的影响。我们采用CS和脂多糖(LPS)两种转基因Cx3cr1gfp/gfp小鼠和原代人内皮细胞和单核细胞急性炎症模型，研究了sCX3CL1介导的CX3CR1+单核细胞的黏附和迁移。测定COPD患者血浆和支气管肺泡灌洗液(BALF)中sCX3CL1水平。CX3CL1脱落和CX3CR1+单核细胞经内皮细胞迁移均可由内毒素和CS引起，AAT可显著抑制其迁移。AAT对单核细胞-内皮细胞黏附和迁移的抑制作用依赖于TACE。与健康对照组相比，COPD患者血浆和BALF中sCX3CL1水平均升高，且与肺气肿的临床参数相关。我们的结果表明，抑制sCX3CL1以及AAT的增加可能是减少急、慢性炎症状态下单核细胞肺过度募集的有效途径。新与新的发现表明，AAT和TACE的其他抑制剂(控制全长Fractalkine(CX3CL1)内皮细胞表达的脱落酶)可能微调CX3CL1-CX3CR1轴，该轴专门参与内皮-单核细胞串扰和白细胞向肺泡腔的募集，这表明AAT和sCX3CL1信号的抑制剂可能被利用来减轻肺部炎症。
Chronic obstructive pulmonary disease (COPD) is characterized by nonresolving inflammation fueled by breach in the endothelial barrier and leukocyte recruitment into the airspaces. Among the ligand-receptor axes that control leukocyte recruitment, the full-length fractalkine ligand (CX3CL1)-receptor (CX3CR1) ensures homeostatic endothelial-leukocyte interactions. Cigarette smoke (CS) exposure and respiratory pathogens increase expression of endothelial sheddases, such as a-disintegrin-and-metalloproteinase-domain 17 (ADAM17, TACE), inhibited by the anti-protease α-1 antitrypsin (AAT). In the systemic endothelium, TACE cleaves CX3CL1 to release soluble CX3CL1 (sCX3CL1). During CS exposure, it is not known whether AAT inhibits sCX3CL1 shedding and CX3CR1+leukocyte transendothelial migration across lung microvasculature. We investigated the mechanism of sCX3CL1 shedding, its role in endothelial-monocyte interactions, and AAT effect on these interactions during acute inflammation. We used two, CS and lipopolysaccharide (LPS) models of acute inflammation in transgenicCx3cr1gfp/gfpmice and primary human endothelial cells and monocytes to study sCX3CL1-mediated CX3CR1+monocyte adhesion and migration. We measured sCX3CL1 levels in plasma and bronchoalveolar lavage (BALF) of individuals with COPD. Both sCX3CL1 shedding and CX3CR1+monocytes transendothelial migration were triggered by LPS and CS exposure in mice, and were significantly attenuated by AAT. The inhibition of monocyte-endothelial adhesion and migration by AAT was TACE-dependent. Compared with healthy controls, sCX3CL1 levels were increased in plasma and BALF of individuals with COPD, and were associated with clinical parameters of emphysema. Our results indicate that inhibition of sCX3CL1 as well as AAT augmentation may be effective approaches to decrease excessive monocyte lung recruitment during acute and chronic inflammatory states.NEW & NOTEWORTHYOur novel findings that AAT and other inhibitors of TACE, the sheddase that controls full-length fractalkine (CX3CL1) endothelial expression, may provide fine-tuning of the CX3CL1-CX3CR1 axis specifically involved in endothelial-monocyte cross talk and leukocyte recruitment to the alveolar space, suggests that AAT and inhibitors of sCX3CL1 signaling may be harnessed to reduce lung inflammation.