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A role for mast cells and mast cell tryptase in driving neutrophil recruitment in LPS-induced lung inflammation via protease-activated receptor 2 in mice.
Inflammation Research ( IF 4.8 ) Pub Date : 2020-07-06 , DOI: 10.1007/s00011-020-01376-4
Aline Dias de Almeida 1 , Irismara Sousa Silva 1 , Weslley Fernandes-Braga 2 , Antônio Carlos Melo LimaFilho 3 , R Odrigo Machado Florentino 3 , Ayslan Barra 1 , Luciana de Oliveira Andrade 4 , M Fátima Leite 3 , Geovanni Dantas Cassali 5 , André Klein 1
Affiliation  

Objective

This study aims to investigate the role of protease-activated receptor (PAR) 2 and mast cell (MC) tryptase in LPS-induced lung inflammation and neutrophil recruitment in the lungs of C57BL/6 mice.

Methods

C57BL/6 mice were pretreated with the PAR2 antagonist ENMD-1068, compound 48/80 or aprotinin prior to intranasal instillation of MC tryptase or LPS. Blood leukocytes, C-X-C motif chemokine ligand (CXCL) 1 production leukocytes recovered from bronchoalveolar lavage fluid (BALF), and histopathological analysis of the lung were evaluated 4 h later. Furthermore, we performed experiments to determine intracellular calcium signaling in RAW 264.7 cells stimulated with LPS in the presence or absence of a protease inhibitor cocktail or ENMD-1068 and evaluated PAR2 expression in the lungs of LPS-treated mice.

Results

Pharmacological blockade of PAR2 or inhibition of proteases reduced neutrophils recovered in BALF and LPS-induced calcium signaling. PAR2 blockade impaired LPS-induced lung inflammation, PAR2 expression in the lung and CXCL1 release in BALF, and increased circulating blood neutrophils. Intranasal instillation of MC tryptase increased the number of neutrophils recovered in BALF, and MC depletion with compound 48/80 impaired LPS-induced neutrophil migration.

Conclusion

Our study provides, for the first time, evidence of a pivotal role for MCs and MC tryptase in neutrophil migration, lung inflammation and macrophage activation triggered by LPS, by a mechanism dependent on PAR2 activation.



中文翻译:

肥大细胞和肥大细胞类胰蛋白酶在通过小鼠蛋白酶激活受体 2 驱动 LPS 诱导的肺部炎症中的中性粒细胞募集中的作用。

客观的

本研究旨在研究蛋白酶激活受体 (PAR) 2 和肥大细胞 (MC) 类胰蛋白酶在 C57BL/6 小鼠肺部 LPS 诱导的肺部炎症和中性粒细胞募集中的作用。

方法

C57BL/6 小鼠在鼻内滴注 MC 类胰蛋白酶或 LPS 之前用 PAR2 拮抗剂 ENMD-1068、化合物 48/80 或抑肽酶预处理。4 小时后评估血液白细胞、从支气管肺泡灌洗液 (BALF) 中回收的 CXC 基序趋化因子配体 (CXCL) 1 生产白细胞和肺的组织病理学分析。此外,我们进行了实验以确定在存在或不存在蛋白酶抑制剂混合物或 ENMD-1068 的情况下用 LPS 刺激的 RAW 264.7 细胞中的细胞内钙信号,并评估了 LPS 处理小鼠肺中的 PAR2 表达。

结果

PAR2 的药理学阻断或蛋白酶的抑制减少了在 BALF 和 LPS 诱导的钙信号中恢复的中性粒细胞。PAR2 阻断会损害 LPS 诱导的肺部炎症、肺中的 PAR2 表达和 BALF 中的 CXCL1 释放,并增加循环血液中的中性粒细胞。MC 类胰蛋白酶的鼻内滴注增加了 BALF 中回收的中性粒细胞数量,并且化合物 48/80 消耗的 MC 会损害 LPS 诱导的中性粒细胞迁移。

结论

我们的研究首次提供了 MC 和 MC 类胰蛋白酶在嗜中性粒细胞迁移、肺部炎症和由 LPS 引发的巨噬细胞激活中起关键作用的证据,其机制依赖于 PAR2 激活。

更新日期:2020-07-06
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