LL-37和瓜氨酸化LL-37可调节IL-17A/ f介导的支气管上皮细胞反应,并选择性抑制Lipocalin-2。

IF 4.4 3区 医学 Q2 IMMUNOLOGY
Anthony Altieri, Dylan Lloyd, Padmanie Ramotar, Anne M van der Does, Mahadevappa Hemshekhar, Neeloffer Mookherjee
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引用次数: 0

摘要

背景:中性粒细胞气道炎症期间,人阳离子抗微生物宿主防御肽LL-37水平在肺部增强。LL-37驱动Th17分化,Th17细胞产生IL-17A和IL-17F,形成具有生物活性的异源二聚体IL-17A/F。虽然IL-17是中性粒细胞气道炎症的关键介质,但LL-37表现出矛盾的功能;LL-37可以根据炎症环境促进和减轻中性粒细胞的募集。在气道炎症的背景下,LL-37对il -17诱导的反应的影响在很大程度上仍然未知。因此,我们研究了人支气管上皮细胞(HBEC)中由IL-17A/F和LL-37相互作用介导的信号中间体和下游反应。由于LL-37可以在气道炎症期间变成瓜氨酸化,我们还研究了LL-37介导的下游反应,并将其与瓜氨酸化的LL-37 (citLL-37)在HBEC中进行了比较。结果:使用基于适配体的蛋白质组学方法,我们确定了在HBEC中响应IL-17A/F而改变的蛋白质。IL-17A/F增强的蛋白主要是中性粒细胞趋化剂,包括趋化因子和与中性粒细胞迁移相关的蛋白,如脂钙素-2 (LCN-2)。我们发现LCN-2的选择性耗竭减轻了中性粒细胞的迁移,从功能上证明了LCN-2是一个关键的中性粒细胞化学引诱剂。我们进一步证明,LL-37和citLL-37选择性地抑制IL-17A/ f诱导的HBEC中LCN-2的丰度。机制研究表明,LL-37和citLL-37抑制IL-17 A/ f介导的C/EBPβ的增强,C/EBPβ是LCN-2产生所需的转录因子。相比之下,LL-37和citLL-37增加了核糖核酸酶regase -1的丰度,regase -1是HBEC中IL-17和LCN-2的负调节因子。在肺中IL-17A/F和中性粒细胞弹性蛋白酶升高的过敏原挑战气道炎症动物模型中,我们证明了CRAMP (LL-37的小鼠同源物)与LCN-2呈负相关。结论:总体而言,我们的研究结果表明,LL-37和citLL-37可以选择性地抑制IL-17A/ f介导的LCN-2的丰度,LCN-2是HBEC中性粒细胞迁移的关键蛋白。这些结果表明,在气道炎症期间,LL-37及其瓜氨酸修饰形式可能负调控il -17介导的中性粒细胞迁移。据我们所知,这是第一个报道LL-37免疫调节功能增强RNA结合蛋白Regnase-1的研究,表明该肽介导了一种转录后作用机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
LL-37 and citrullinated-LL-37 modulate IL-17A/F-mediated responses and selectively suppress Lipocalin-2 in bronchial epithelial cells.

Background: Levels of the human cationic antimicrobial host defence peptide LL-37 are enhanced in the lungs during neutrophilic airway inflammation. LL-37 drives Th17 differentiation, and Th17 cells produce IL-17A and IL-17F which form the biologically active heterodimer IL-17A/F. While IL-17 is a critical mediator of neutrophilic airway inflammation, LL-37 exhibits contradictory functions; LL-37 can both promote and mitigate neutrophil recruitment depending on the inflammatory milieu. The impact of LL-37 on IL-17-induced responses in the context of airway inflammation remains largely unknown. Therefore, we examined signaling intermediates and downstream responses mediated by the interplay of IL-17A/F and LL-37 in human bronchial epithelial cells (HBEC). As LL-37 can become citrullinated during airway inflammation, we also examined LL-37-mediated downstream responses compared to that with citrullinated LL-37 (citLL-37) in HBEC.

Results: Using an aptamer-based proteomics approach, we identified proteins that are altered in response to IL-17A/F in HBEC. Proteins enhanced in response to IL-17A/F were primarily neutrophil chemoattractants, including chemokines and proteins associated with neutrophil migration such as lipocalin-2 (LCN-2). We showed that selective depletion of LCN-2 mitigates neutrophil migration, functionally demonstrating LCN-2 as a critical neutrophil chemoattractant. We further demonstrated that LL-37 and citLL-37 selectively suppress IL-17A/F-induced LCN-2 abundance in HBEC. Mechanistic studies revealed that LL-37 and citLL-37 suppresses IL-17 A/F-mediated enhancement of C/EBPβ, a transcription factor required for LCN-2 production. In contrast, LL-37 and citLL-37 enhance the abundance of ribonuclease Regnase-1, which is a negative regulator of IL-17 and LCN-2 in HBEC. In an animal model of allergen-challenged airway inflammation with elevated IL-17A/F and neutrophil elastase in the lungs, we demonstrated that CRAMP (mouse orthologue of LL-37) negatively correlates with LCN-2.

Conclusions: Overall, our findings showed that LL-37 and citLL-37 can selectively suppress the abundance of IL-17A/F-mediated LCN-2, a protein that is critical for neutrophil migration in HBEC. These results suggest that LL-37, and its modified citrullinated form, have the potential to negatively regulate IL-17-mediated neutrophil migration during airway inflammation. To our knowledge, this is the first study to report that the immunomodulatory function of LL-37 enhances the RNA binding protein Regnase-1, suggesting that a post-transcriptional mechanism of action is mediated by the peptide.

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来源期刊
CiteScore
7.90
自引率
0.00%
发文量
18
审稿时长
>12 weeks
期刊介绍: Journal of Inflammation welcomes research submissions on all aspects of inflammation. The five classical symptoms of inflammation, namely redness (rubor), swelling (tumour), heat (calor), pain (dolor) and loss of function (functio laesa), are only part of the story. The term inflammation is taken to include the full range of underlying cellular and molecular mechanisms involved, not only in the production of the inflammatory responses but, more importantly in clinical terms, in the healing process as well. Thus the journal covers molecular, cellular, animal and clinical studies, and related aspects of pharmacology, such as anti-inflammatory drug development, trials and therapeutic developments. It also considers publication of negative findings. Journal of Inflammation aims to become the leading online journal on inflammation and, as online journals replace printed ones over the next decade, the main open access inflammation journal. Open access guarantees a larger audience, and thus impact, than any restricted access equivalent, and increasingly so, as the escalating costs of printed journals puts them outside University budgets. The unrestricted access to research findings in inflammation aids in promoting dynamic and productive dialogue between industrial and academic members of the inflammation research community, which plays such an important part in the development of future generations of anti-inflammatory therapies.
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