Extracellular vesicle as biomarkers in NSAID-exacerbated respiratory disease

IF 4.6 2区 医学 Q2 ALLERGY
Isaac Kirubakaran Sundar
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We commend the authors for their exciting research into the role of extracellular vesicle (EV) miRNAs in mediating aberrant macrophage responses in NSAID-exacerbated respiratory disease (N-ERD).<span><sup>1</sup></span> The authors evaluated EVs from sputum and conditioned medium of the nasal polyp or turbinate tissues from patients with chronic rhinosinusitis with nasal polyps (CRSwNP), N-ERD, and healthy controls.<span><sup>1</sup></span> Small RNA sequencing revealed intriguing and contrasting miRNA profiles in sputum EVs from N-ERD patients compared to previous reports on BAL fluid EVs from asthmatics,<span><sup>2</sup></span> and nasal tissue from CRSwNP patients.<span><sup>3</sup></span> Specifically, let-7 family miRNAs were upregulated while miR-155 was downregulated in N-ERD sputum EVs.<span><sup>1</sup></span> These distinct miRNA signatures suggest the source of EVs dictates the enrichment of miRNAs in healthy versus N-ERD samples. 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To support the RNA-seq data presented here, direct validation of the miRNA signature and associated mRNA targets in the N-ERD groups is necessary. We have pointed out the strengths and weaknesses of this study below. Overall, we advise caution in interpreting these findings until they are validated in a larger sample cohort by the authors and readers.</p><p>This study sheds light on the pathogenesis of N-ERD, which is a severe form of asthma. The study analyzed the RNA-seq data from MDM treated with sputum EVs from healthy, CRSwNP, and N-ERD patients, as well as small RNA-seq of sputum and tissue culture supernatant EVs from healthy turbinate or nasal polyp tissue (N-ERD). Although the authors performed a comprehensive analysis of EV miRNA profiling and in vitro experiments using MDM, the identified EV-specific miRNAs (upregulated miR-125a and let-7 family) enriched in N-ERD sputum EVs induced M2 polarization and enhanced proinflammatory and tissue remodeling functions. 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Overall, while this study made important contributions, integrating past literature and transcriptomic datasets within the study could provide deeper novel insights into miRNA-mediated mechanisms in N-ERD.</p><p>Asthma is a complex, heterogeneous disease with diverse phenotypes and endotypes, which makes it difficult to diagnose and treat.<span><sup>6</sup></span> The “one-airway-one-disease” theory suggests that the upper and lower airways share similar characteristics, but the mechanisms behind asthma are diverse and sometimes overlap.<span><sup>7</sup></span> Recently, researchers have found that studying EVs through liquid biopsy can provide new insights into how they signal and regulate lung health and disease.<span><sup>8</sup></span> Identifying new EV biomarkers that can distinguish asthma phenotypes and endotypes<span><sup>9</sup></span> is necessary because current biomarkers are not sensitive and specific.</p><p>However, this study has some limitations. The authors used RNA-seq and small RNA-seq to identify genes and miRNAs in MDM treated with sputum EVs from healthy controls and patients with N-ERD (<i>n</i> = 2). The exploratory studies used pooled sputum EVs from N-ERD patients (<i>n</i> = 4) and healthy controls (<i>n</i> = 10), as well as nasal tissue culture supernatant EVs from healthy controls (<i>n</i> = 1) and N-ERD patients (<i>n</i> = 4), with very small sample sizes. This raises concerns about whether these findings can be reproduced in a larger validation cohort that compares healthy controls, CRSwNP, and N-ERD patients. This study did not provide detailed clinical characteristics of the healthy controls, N-ERD patients, and CRSwNP patients, and relevant variables were omitted, including medication use, comorbidities, and disease severity, which may affect the EV miRNA signatures identified. The supporting experimental evidence was obtained using cell culture models with pooled EV samples and MDM from patients. 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引用次数: 0

Abstract

We found the recent Allergy article titled “Extracellular vesicle miRNAs drive aberrant macrophage responses in NSAID-exacerbated respiratory disease” fascinating. We commend the authors for their exciting research into the role of extracellular vesicle (EV) miRNAs in mediating aberrant macrophage responses in NSAID-exacerbated respiratory disease (N-ERD).1 The authors evaluated EVs from sputum and conditioned medium of the nasal polyp or turbinate tissues from patients with chronic rhinosinusitis with nasal polyps (CRSwNP), N-ERD, and healthy controls.1 Small RNA sequencing revealed intriguing and contrasting miRNA profiles in sputum EVs from N-ERD patients compared to previous reports on BAL fluid EVs from asthmatics,2 and nasal tissue from CRSwNP patients.3 Specifically, let-7 family miRNAs were upregulated while miR-155 was downregulated in N-ERD sputum EVs.1 These distinct miRNA signatures suggest the source of EVs dictates the enrichment of miRNAs in healthy versus N-ERD samples. Additionally, in vitro experiments supported a role for let-7 family miRNAs in promoting M2 macrophage polarization, which limits cytokine responses triggered by EVs in monocyte-derived macrophages (MDM). This implicates aberrant EV miRNA profiles contributing to N-ERD pathogenesis.

The results obtained from small RNA sequencing analysis are interesting, but the authors have not verified their findings through alternative methods or a replication cohort of samples. They have not provided sufficient details about the total EV concentration and EV protein abundance across the three groups (healthy, CRSwNP, and N-ERD) and the sample types analyzed (sputum vs. turbinate tissue/nasal polyp tissue). It is also unclear whether the EV miRNAs identified match previous findings in similar sample types from asthma and IPF.4, 5 Moreover, the use of pooled samples and a relatively small sample size for the RNA-sequencing and interpretation is surprising. To support the RNA-seq data presented here, direct validation of the miRNA signature and associated mRNA targets in the N-ERD groups is necessary. We have pointed out the strengths and weaknesses of this study below. Overall, we advise caution in interpreting these findings until they are validated in a larger sample cohort by the authors and readers.

This study sheds light on the pathogenesis of N-ERD, which is a severe form of asthma. The study analyzed the RNA-seq data from MDM treated with sputum EVs from healthy, CRSwNP, and N-ERD patients, as well as small RNA-seq of sputum and tissue culture supernatant EVs from healthy turbinate or nasal polyp tissue (N-ERD). Although the authors performed a comprehensive analysis of EV miRNA profiling and in vitro experiments using MDM, the identified EV-specific miRNAs (upregulated miR-125a and let-7 family) enriched in N-ERD sputum EVs induced M2 polarization and enhanced proinflammatory and tissue remodeling functions. This provides initial mechanistic insights into N-ERD pathobiology that warrant further exploration and validation. However, the study did not discuss known EV miRNA findings from asthma studies nor integrate the RNA-seq and small RNA-seq data from MDM experiments to directly relate target genes and associated miRNAs to cell type-specific roles in N-ERD versus healthy controls. Overall, while this study made important contributions, integrating past literature and transcriptomic datasets within the study could provide deeper novel insights into miRNA-mediated mechanisms in N-ERD.

Asthma is a complex, heterogeneous disease with diverse phenotypes and endotypes, which makes it difficult to diagnose and treat.6 The “one-airway-one-disease” theory suggests that the upper and lower airways share similar characteristics, but the mechanisms behind asthma are diverse and sometimes overlap.7 Recently, researchers have found that studying EVs through liquid biopsy can provide new insights into how they signal and regulate lung health and disease.8 Identifying new EV biomarkers that can distinguish asthma phenotypes and endotypes9 is necessary because current biomarkers are not sensitive and specific.

However, this study has some limitations. The authors used RNA-seq and small RNA-seq to identify genes and miRNAs in MDM treated with sputum EVs from healthy controls and patients with N-ERD (n = 2). The exploratory studies used pooled sputum EVs from N-ERD patients (n = 4) and healthy controls (n = 10), as well as nasal tissue culture supernatant EVs from healthy controls (n = 1) and N-ERD patients (n = 4), with very small sample sizes. This raises concerns about whether these findings can be reproduced in a larger validation cohort that compares healthy controls, CRSwNP, and N-ERD patients. This study did not provide detailed clinical characteristics of the healthy controls, N-ERD patients, and CRSwNP patients, and relevant variables were omitted, including medication use, comorbidities, and disease severity, which may affect the EV miRNA signatures identified. The supporting experimental evidence was obtained using cell culture models with pooled EV samples and MDM from patients. More studies using relevant in vivo models could strengthen these findings, provide mechanistic insights, and identify potential therapeutic targets specific to N-ERD and CRSwNP.

The authors of this study did not functionally validate their findings beyond discussing the potential signaling pathways that may have contributed to the aberrant activation of macrophages and the mediator response observed in N-ERD. Therefore, the findings reported in this study are specific to N-ERD and should be interpreted with caution as they may not apply to other forms of asthma or respiratory diseases. Phenotypic differences due to age and sex/gender also likely play a role. To strengthen the exploratory analysis of small RNAs in EVs, their associated target genes, and their functional contributions to the pathobiology of N-ERD and CRSwNP, it would be worthwhile for the authors to validate these findings using easily accessible samples from healthy controls, N-ERD, and CRSwNP patients with detailed clinical characterization. Future research should focus on using easily accessible liquid biopsy samples from N-ERD and CRSwNP to characterize unique EV miRNA as biomarkers for asthma phenotypes/endotypes. This would enable the development of new strategies to target EV miRNAs to modulate aberrant macrophage activation and associate inflammatory signaling that plays a crucial role in chronic airway disease pathobiology.

Isaac Kirubakaran Sundar: Writing—original draft; writing—review & editing.

The author declares no conflicts of interest.

National Heart, Lung, and Blood Institute, R01HL142543; National Institute of General Medical Sciences, K-INBRE P20 GM103418; University of Kansas Medical Center, School of Medicine, Internal Medicine Start-Up Funds.

细胞外囊泡作为非甾体抗炎药加重呼吸道疾病的生物标志物
我们发现最近一篇题为“细胞外囊泡miRNAs驱动非甾体抗炎药加重呼吸系统疾病的异常巨噬细胞反应”的过敏文章很吸引人。我们赞扬作者对细胞外囊泡(EV) miRNAs在介导非甾体抗炎药加重呼吸系统疾病(N-ERD)中巨噬细胞异常反应中的作用的令人兴奋的研究作者评估了慢性鼻窦炎合并鼻息肉患者(CRSwNP)、N-ERD和健康对照者的痰液和鼻息肉或鼻甲组织条件培养基中的ev小RNA测序结果显示,N-ERD患者的痰中ev与先前报道的哮喘患者的BAL液中ev和CRSwNP患者的鼻组织中ev的miRNA谱存在有趣的差异具体来说,在N-ERD痰样ev中,let-7家族mirna上调,miR-155下调这些不同的miRNA特征表明ev的来源决定了健康和N-ERD样品中miRNA的富集。此外,体外实验支持let-7家族mirna在促进M2巨噬细胞极化中的作用,这限制了ev在单核细胞源性巨噬细胞(MDM)中引发的细胞因子反应。这意味着异常的EV miRNA谱与N-ERD发病机制有关。从小RNA测序分析中获得的结果很有趣,但作者尚未通过替代方法或样本复制队列验证他们的发现。他们没有提供关于三组(健康组、CRSwNP组和N-ERD组)的总EV浓度和EV蛋白丰度以及分析的样本类型(痰与鼻甲组织/鼻息肉组织)的足够细节。此外,尚不清楚所鉴定的EV mirna是否与先前在哮喘和ipf类似样本类型中的发现相匹配。此外,使用汇总样本和相对较小的样本量进行rna测序和解释令人惊讶。为了支持本文提供的RNA-seq数据,有必要在N-ERD组中直接验证miRNA特征和相关mRNA靶标。我们在下面指出了本研究的优点和缺点。总之,在作者和读者在更大的样本队列中验证这些发现之前,我们建议谨慎解释这些发现。这项研究揭示了N-ERD的发病机制,N-ERD是哮喘的一种严重形式。该研究分析了健康、CRSwNP和N-ERD患者的痰中ev治疗MDM的RNA-seq数据,以及健康鼻甲或鼻息肉组织(N-ERD)的痰和组织培养上清ev的小RNA-seq数据。尽管作者对EV miRNA谱进行了全面分析,并使用MDM进行了体外实验,但在N-ERD痰EV中富集的EV特异性miRNA(上调的miR-125a和let-7家族)诱导M2极化并增强了促炎和组织重塑功能。这为N-ERD病理生物学提供了初步的机制见解,值得进一步探索和验证。然而,该研究没有讨论哮喘研究中已知的EV miRNA发现,也没有整合MDM实验中的RNA-seq和小RNA-seq数据,直接将靶基因和相关miRNA与N-ERD与健康对照中细胞类型特异性作用联系起来。总的来说,尽管这项研究做出了重要贡献,但将过去的文献和转录组学数据集整合到研究中,可以为研究mirna介导的N-ERD机制提供更深入的新见解。5 .哮喘是一种复杂的异质性疾病,具有多种表型和内源性,给诊断和治疗带来了困难“一种气道一种疾病”理论认为,上呼吸道和下呼吸道具有相似的特征,但哮喘背后的机制是多种多样的,有时是重叠的最近,研究人员发现,通过液体活检研究电动汽车可以为它们如何发出信号并调节肺部健康和疾病提供新的见解由于目前的生物标志物不敏感和特异性,有必要鉴定出能够区分哮喘表型和内型的新的EV生物标志物。然而,本研究也有一定的局限性。作者使用RNA-seq和小RNA-seq来鉴定健康对照组和n - erd患者(n = 2)的痰中ev治疗MDM的基因和mirna。探索性研究收集了n - erd患者(n = 4)和健康对照组(n = 10)的痰中ev,以及健康对照组(n = 1)和n - erd患者(n = 4)的鼻组织培养上清ev,样本量非常小。这引起了人们的关注,这些发现是否可以在更大的验证队列中重现,比较健康对照组、CRSwNP和N-ERD患者。 本研究没有提供健康对照、N-ERD患者和CRSwNP患者的详细临床特征,并且省略了相关变量,包括药物使用、合并症和疾病严重程度,这些变量可能会影响所识别的EV miRNA特征。通过细胞培养模型和患者的EV样本和MDM获得支持性实验证据。更多使用相关体内模型的研究可以加强这些发现,提供机制见解,并确定针对N-ERD和CRSwNP的潜在治疗靶点。除了讨论可能导致巨噬细胞异常激活的潜在信号通路和在N-ERD中观察到的介质反应外,本研究的作者没有从功能上验证他们的发现。因此,本研究报告的结果仅针对N-ERD,应谨慎解释,因为它们可能不适用于其他形式的哮喘或呼吸系统疾病。由年龄和性别引起的表型差异也可能起作用。为了加强对ev中的小rna及其相关靶基因的探索性分析,以及它们对N-ERD和CRSwNP病理生物学的功能贡献,作者有必要使用具有详细临床特征的健康对照、N-ERD和CRSwNP患者的易于获取的样本来验证这些发现。未来的研究应侧重于使用易于获取的N-ERD和CRSwNP液体活检样本来表征独特的EV miRNA作为哮喘表型/内窥镜的生物标志物。这将有助于开发针对EV mirna的新策略,以调节巨噬细胞的异常激活和相关的炎症信号,这在慢性气道疾病的病理生物学中起着至关重要的作用。艾萨克·基鲁巴卡兰·桑达尔:写作-原稿;writing-review,编辑。作者声明无利益冲突。国家心肺血液研究所,R01HL142543;国家普通医学科学研究所,K-INBRE P20 GM103418;堪萨斯大学医学中心医学院内科启动基金。
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
Clinical and Translational Allergy
Clinical and Translational Allergy Immunology and Microbiology-Immunology
CiteScore
7.50
自引率
4.50%
发文量
117
审稿时长
12 weeks
期刊介绍: Clinical and Translational Allergy, one of several journals in the portfolio of the European Academy of Allergy and Clinical Immunology, provides a platform for the dissemination of allergy research and reviews, as well as EAACI position papers, task force reports and guidelines, amongst an international scientific audience. Clinical and Translational Allergy accepts clinical and translational research in the following areas and other related topics: asthma, rhinitis, rhinosinusitis, drug hypersensitivity, allergic conjunctivitis, allergic skin diseases, atopic eczema, urticaria, angioedema, venom hypersensitivity, anaphylaxis, food allergy, immunotherapy, immune modulators and biologics, animal models of allergic disease, immune mechanisms, or any other topic related to allergic disease.
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