IL1RAP expression and the enrichment of IL-33 activation signatures in severe neutrophilic asthma.
IL1RAP expression and the enrichment of IL-33 activation signatures in severe neutrophilic asthma.
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重症中性粒细胞哮喘患者IL-1RAP的表达及IL-33激活信号的丰富
DOI：
10.1111/all.15487
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发表时间：
2023-01
期刊：
影响因子：
12.4
通讯作者：
Adcock, Ian M.
中科院分区：
文献类型：
--
作者：
Badi, Yusef Eamon;Salcman, Barbora;Taylor, Adam;Rana, Batika;Kermani, Nazanin Zounemat;Riley, John H.;Worsley, Sally;Mumby, Sharon;Dahlen, Sven-Eric;Cousins, David;Silvia, Bulfone-Paus;Affleck, Karen;Chung, Kian Fan;Bates, Stewart;Adcock, Ian M.
白介素33是2型(T2)嗜酸性炎症的上游调节因子，已被认为是某些哮喘表型的关键驱动因素。从IL-33刺激细胞的体外研究中获得基因特征，并使用这些特征来确定哮喘患者中与IL-33相关的浓缩模式。IL-33刺激下游的信号来自我们对人类肥大细胞的体外研究，以及体外刺激的人嗜碱性粒细胞、2型固有淋巴样细胞(ILC2)、调节性T细胞(Treg)和内皮细胞的公共数据集。根据哮喘严重程度、痰粒细胞状态和预先定义的分子表型，采用基因集变异分析(GSVA)检测U-BIOPRED和AEPT痰标本转录产物，以确定每个征象的浓缩分数(ES)。IL-33激活的基因特征是细胞特异性的，基因重叠很少。然而，个体特征与相似的信号通路(肿瘤坏死因子、核因子κB、IL-17和JAK/STAT信号)和免疫细胞分化途径(Th17、Th1和Th2分化)有关。IL-33激活基因特征的ES在哮喘痰中显著丰富，特别是在中性粒细胞和混合粒细胞表型的患者中。IL-33mRNA在哮喘患者中表达不高，而IL-33受体IL-1RL1mRNA在重度嗜酸性哮喘患者痰中表达上调。IL1RL1共同受体IL1RAP的mRNA在重度中性粒细胞哮喘和混合粒细胞哮喘中的表达最强。IL-33激活的基因特征在中性粒细胞和混合粒细胞哮喘中升高，与IL1RAP共同受体的表达相对应。这建议将T2低哮喘纳入抗IL-33试验。IL-33刺激人肥大细胞、嗜碱性粒细胞、ILC2细胞和HUVECs产生不同的基因表达模式，但激活相似的途径。我们产生了IL-33激活的基因标记，并使用GSVA，并在中性粒细胞和混合粒细胞哮喘患者中显示了这些标记的丰富。缩写：BAS，嗜碱性粒细胞；HUVECs，人脐静脉内皮细胞；IL，白细胞；ILC2，2型固有淋巴样细胞；IL1RAP，IL-1受体辅助蛋白；JAK，Janus激酶；MC，肥大细胞；STAT，信号转导和转录激活因子；Th，辅助性T细胞；肿瘤坏死因子
Interleukin (IL)‐33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes. To derive gene signatures from in vitro studies of IL‐33‐stimulated cells and use these to determine IL‐33‐associated enrichment patterns in asthma. Signatures downstream of IL‐33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells. Gene Set Variation Analysis (GSVA) was used to probe U‐BIOPRED and ADEPT sputum transcriptomics to determine enrichment scores (ES) for each signature according to asthma severity, sputum granulocyte status and previously defined molecular phenotypes. IL‐33‐activated gene signatures were cell‐specific with little gene overlap. Individual signatures, however, were associated with similar signalling pathways (TNF, NF‐κB, IL‐17 and JAK/STAT signalling) and immune cell differentiation pathways (Th17, Th1 and Th2 differentiation). ES for IL‐33‐activated gene signatures were significantly enriched in asthmatic sputum, particularly in patients with neutrophilic and mixed granulocytic phenotypes. IL‐33 mRNA expression was not elevated in asthma whereas the expression of mRNA for IL1RL1, the IL‐33 receptor, was up‐regulated in the sputum of severe eosinophilic asthma. The mRNA expression for IL1RAP, the IL1RL1 co‐receptor, was greatest in severe neutrophilic and mixed granulocytic asthma. IL‐33‐activated gene signatures are elevated in neutrophilic and mixed granulocytic asthma corresponding with IL1RAP co‐receptor expression. This suggests incorporating T2‐low asthma in anti‐IL‐33 trials. Stimulation of human mast cells, basophils, ILC2 cells and HUVECs with IL‐33 generates distinct gene expression patterns but similar pathways are activated. We produced IL‐33‐activated gene signatures and used GSVA and showed enrichment of these signatures in patients with neutrophilic and mixed granulocytic asthma. These patients had the highest expression of the IL‐33 receptor co‐receptor IL1RAP.Abbreviations: BAS, basophil; HUVECs, human umbilical vein endothelial cells; IL, interleukin; ILC2, type 2 innate lymphoid cell; IL1RAP, IL‐1 receptor accessory protein; JAK, Janus kinase; MC, mast cell; STAT, signal transducer and activator of transcription; Th, T helper; TNF, tumor necrosis factor
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影响因子：
30.5
作者：
Hojen, Jesper Falkesgaard;Kristensen, Marie Louise Vindvad;Dinarello, Charles A.
通讯作者：
Dinarello, Charles A.
DOI：
10.2147/copd.s99547
发表时间：
2016
影响因子：
2.8
作者：
Lacedonia D;Carpagnano GE;Trotta T;Palladino GP;Panaro MA;Zoppo LD;Foschino Barbaro MP;Porro C
通讯作者：
Porro C
影响因子：
14.2
作者：
Ketelaar, Maria E.;Portelli, Michael A.;Nawijn, Martijn C.
通讯作者：
Nawijn, Martijn C.
影响因子：
6.1
作者：
Ketelaar, M. E.;Nawijn, M. C.;Sayers, I.
通讯作者：
Sayers, I.
影响因子：
12.4
作者：
George, Leena;Taylor, Adam R.;Brightling, Christopher E.
通讯作者：
Brightling, Christopher E.