Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.
Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.
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DOI：
10.1016/j.jaci.2022.04.034
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发表时间：
2022-10
影响因子：
14.2
通讯作者：
Bleier, Benjamin S.
中科院分区：
文献类型：
--
作者：
Nocera, Angela L.;Mueller, Sarina K.;Workman, Alan D.;Wu, Dawei;McDonnell, Kristen;Sadow, Peter M.;Amiji, Mansoor M.;Bleier, Benjamin S.
关键词：
胱抑素SN （CST1）和胱抑素SA （CST2）是半胱氨酸蛋白酶抑制剂，可防止过敏原、病毒和细菌蛋白酶。半胱抑素在变应性鼻炎和慢性鼻窦炎伴鼻息肉（CRSwNP）中过度表达；然而，它们在促进2型炎症中的作用仍然知之甚少。本研究的目的是利用整合多组学和小鼠暴露模型来探索CRSwNP中胱抑素过表达与2型炎症之间的联系。在这项机构审查委员会和机构动物护理和使用委员会批准的研究中，我们通过匹配的全外显子组测序、转录组学、蛋白质组学、翻译后修饰、组织学、功能和生物信息学分析，比较了CRSwNP和对照组（每组n = 10）的组织、外显子体和粘液CST1和CST2。C57/BL6小鼠在存在或不存在上皮细胞ABCB1a敲除的情况下，经鼻给药3.9 μg/mL CST1或PBS 5 ~ 18天。采用Quansys multiplex法或elisa法定量检测炎症细胞因子。在定量的1305个蛋白中，CST1和CST2是组织、外泌体和粘液样本中过度表达最多的蛋白酶抑制剂；它们局限于上皮。在息肉组织中发现了多种翻译后修饰。外泌体CST1和CST2与嗜酸性粒细胞和Lund-Mackay评分呈显著相关性。小鼠2型细胞因子分泌和TH2细胞浸润在CST1暴露后呈时间依赖性增加，并被上皮细胞因子分泌调节因子ABCB1a敲除。CST1是CRSwNP中上皮源性2型炎症的有效上游启动物。针对CST活性及其相关的翻译后修饰的治疗策略值得进一步研究。
Cystatin SN (CST1) and cystatin SA (CST2) are cysteine protease inhibitors that protect against allergen, viral, and bacterial proteases. Cystatins are overexpressed in the setting of allergic rhinitis and chronic rhinosinusitis with nasal polyps (CRSwNP); however, their role in promoting type 2 inflammation remains poorly characterized. The purpose of this study was to use integrated poly-omics and a murine exposure model to explore the link between cystatin overexpression in CRSwNP and type 2 inflammation. In this institutional review board– and institutional animal care and use committee–approved study, we compared tissue, exosome, and mucus CST1 and CST2 between CRSwNP and controls (n = 10 per group) by using matched whole exome sequencing, transcriptomic, proteomic, posttranslational modification, histologic, functional, and bioinformatic analyses. C57/BL6 mice were dosed with 3.9 μg/mL of CST1 or PBS intranasally for 5 to 18 days in the presence or absence of epithelial ABCB1a knockdown. Inflammatory cytokines were quantified by using Quansys multiplex assays or ELISAs. Of the 1305 proteins quantified, CST1 and CST2 were among the most overexpressed protease inhibitors in tissue, exosome, and mucus samples; they were localized to the epithelial layer. Multiple posttranslational modifications were identified in the polyp tissue. Exosomal CST1 and CST2 were strongly and significantly correlated with eosinophils and Lund-Mackay scores. Murine type 2 cytokine secretion and TH2 cell infiltration increased in a time-dependent manner following CST1 exposure and was abrogated by epithelial knockdown of ABCB1a, a regulator of epithelial cytokine secretion. CST1 is a potent upstream initiator of epithelial-derived type 2 inflammation in CRSwNP. Therapeutic strategies targeting CST activity and its associated posttranslational modifications deserve further interrogation.
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影响因子：
3.7
作者：
Gold L;Ayers D;Bertino J;Bock C;Bock A;Brody EN;Carter J;Dalby AB;Eaton BE;Fitzwater T;Flather D;Forbes A;Foreman T;Fowler C;Gawande B;Goss M;Gunn M;Gupta S;Halladay D;Heil J;Heilig J;Hicke B;Husar G;Janjic N;Jarvis T;Jennings S;Katilius E;Keeney TR;Kim N;Koch TH;Kraemer S;Kroiss L;Le N;Levine D;Lindsey W;Lollo B;Mayfield W;Mehan M;Mehler R;Nelson SK;Nelson M;Nieuwlandt D;Nikrad M;Ochsner U;Ostroff RM;Otis M;Parker T;Pietrasiewicz S;Resnicow DI;Rohloff J;Sanders G;Sattin S;Schneider D;Singer B;Stanton M;Sterkel A;Stewart A;Stratford S;Vaught JD;Vrkljan M;Walker JJ;Watrobka M;Waugh S;Weiss A;Wilcox SK;Wolfson A;Wolk SK;Zhang C;Zichi D
通讯作者：
Zichi D
影响因子：
3.7
作者：
Imoto Y;Tokunaga T;Matsumoto Y;Hamada Y;Ono M;Yamada T;Ito Y;Arinami T;Okano M;Noguchi E;Fujieda S
通讯作者：
Fujieda S
影响因子：
120.7
作者：
Bachert, Claus;Mannent, Leda;Sutherland, E. Rand
通讯作者：
Sutherland, E. Rand
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
5.6
作者：
Fábián TK;Hermann P;Beck A;Fejérdy P;Fábián G
通讯作者：
Fábián G