Human Host Defense Peptide LL-37 Suppresses TNFα-Mediated Matrix Metalloproteinases MMP9 and MMP13 in Human Bronchial Epithelial Cells.

IF 4.7 3区 医学 Q2 IMMUNOLOGY
Journal of Innate Immunity Pub Date : 2024-01-01 Epub Date: 2024-03-12 DOI:10.1159/000537775
Anthony Altieri, Courtney Lynn Marshall, Padmanie Ramotar, Dylan Lloyd, Mahadevappa Hemshekhar, Victor Spicer, Anne M van der Does, Neeloffer Mookherjee
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引用次数: 0

Abstract

Introduction: TNFα-inducible matrix metalloproteinases play a critical role in the process of airway remodeling in respiratory inflammatory disease including asthma. The cationic host defense peptide LL-37 is elevated in the lungs during airway inflammation. However, the impact of LL-37 on TNFα-driven processes is not well understood. Here, we examined the effect of LL-37 on TNFα-mediated responses in human bronchial epithelial cells (HBECs).

Methods: We used a slow off-rate modified aptamer-based proteomics approach to define the HBEC proteome altered in response to TNFα. Abundance of selected protein candidates and signaling intermediates was examined using immunoassays, ELISA and Western blots, and mRNA abundance was examined by qRT-PCR.

Results: Proteomics analysis revealed that 124 proteins were significantly altered, 12 proteins were enhanced by ≥2-fold compared to unstimulated cells, in response to TNFα. MMP9 was the topmost increased protein in response to TNFα, enhanced by ∼10-fold, and MMP13 was increased by ∼3-fold, compared to unstimulated cells. Furthermore, we demonstrated that LL-37 significantly suppressed TNFα-mediated MMP9 and MMP13 in HBEC. Mechanistic data revealed that TNFα-mediated MMP9 and MMP13 production is controlled by SRC kinase and that LL-37 enhances related upstream negative regulators, namely, phospho-AKT (T308) and TNFα-mediated TNFAIP3 or A20.

Conclusions: The findings of this study suggest that LL-37 may play a role in intervening in the process of airway remodeling in chronic inflammatory respiratory disease such as asthma.

人类宿主防御肽 LL-37 可抑制 TNFα 介导的人类支气管上皮细胞基质金属蛋白酶 MMP9 和 MMP13。
导言:TNFα 诱导的基质金属蛋白酶(MMP)在包括哮喘在内的呼吸道炎症疾病的气道重塑过程中发挥着关键作用。阳离子宿主防御肽(CHDP)LL-37 在气道炎症期间会在肺部升高。然而,LL-37 对 TNFα 驱动过程的影响尚不十分清楚。在此,我们研究了 LL-37 对人支气管上皮细胞(HBEC)中 TNFα 介导的反应的影响:方法:我们使用了一种基于慢脱率修饰质粒的蛋白质组学方法来确定 HBEC 蛋白质组在 TNFα 反应中的变化。结果:蛋白质组学分析显示,124 种候选蛋白质和信号转导中间体的丰度发生了变化:蛋白质组学分析表明,与未受刺激的细胞相比,124种蛋白质在TNFα作用下发生了显著变化,其中12种蛋白质增强了≥2倍。与未刺激细胞相比,MMP9是对TNFα反应增加最多的蛋白,增加了约10倍,MMP13增加了约3倍。此外,我们还证明 LL-37 能显著抑制 TNFα 介导的 HBEC 中的 MMP9 和 MMP13。机理数据显示,TNFα介导的 MMP9 和 MMP13 的产生受 SRC 激酶控制,LL-37 可增强相关的上游负调控因子,即 phosphoAKT(T308) 和 TNFα 介导的 TNFAIP3 或 A20:本研究结果表明,LL-37 可在干预哮喘等慢性炎症性呼吸道疾病的气道重塑过程中发挥作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Innate Immunity
Journal of Innate Immunity 医学-免疫学
CiteScore
10.50
自引率
1.90%
发文量
35
审稿时长
7.5 months
期刊介绍: The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.
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