半胱氨酸蛋白酶抑制剂 SN 是慢性鼻-鼻窦炎中上皮源性 2 型炎症的有效上游启动子。
Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis.
机构信息
Department of Otolaryngology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Mass; Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Mass.
Department of Otolaryngology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Mass; Department of Otolaryngology/Head and Neck Surgery, University of Erlangen-Nuremberg, Nuremberg, Germany.
出版信息
J Allergy Clin Immunol. 2022 Oct;150(4):872-881. doi: 10.1016/j.jaci.2022.04.034. Epub 2022 May 31.
BACKGROUND
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.
OBJECTIVE
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.
METHODS
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.
RESULTS
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 T2 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.
CONCLUSION
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.
背景
半胱氨酸蛋白酶抑制剂 SN（CST1）和半胱氨酸蛋白酶抑制剂 SA（CST2）是一种能够抵御过敏原、病毒和细菌蛋白酶的半胱氨酸蛋白酶抑制剂。在变应性鼻炎和伴有鼻息肉的慢性鼻-鼻窦炎（CRSwNP）中，胱抑素过度表达；然而，它们在促进 2 型炎症中的作用仍未得到充分描述。
目的
本研究旨在通过整合多组学和小鼠暴露模型来探讨 CRSwNP 中胱抑素过度表达与 2 型炎症之间的联系。
方法
在这项经过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 10 例）组织、外泌体和黏液 CST1 和 CST2。C57/BL6 小鼠用 3.9 μg/mL 的 CST1 或 PBS 经鼻腔给药 5 至 18 天，同时进行上皮 ABCB1a 敲低或不敲低。通过 Quansys 多重分析或 ELISA 定量检测炎症细胞因子。
结果
在所定量的 1305 种蛋白质中，CST1 和 CST2 是组织、外泌体和黏液样本中表达最丰富的蛋白酶抑制剂之一；它们定位于上皮层。在息肉组织中鉴定出多种翻译后修饰。外泌体 CST1 和 CST2 与嗜酸性粒细胞和 Lund-Mackay 评分呈强烈且显著相关。CST1 暴露后，小鼠 2 型细胞因子分泌和 T2 细胞浸润呈时间依赖性增加，上皮 ABCB1a 敲低可阻断这种增加，ABCB1a 是上皮细胞因子分泌的调节剂。
结论
CST1 是 CRSwNP 中上皮源性 2 型炎症的一个强有力的上游启动子。针对 CST 活性及其相关翻译后修饰的治疗策略值得进一步研究。
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