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SARS-CoV-2 触发肥大细胞快速脱颗粒，导致肺泡上皮炎症和肺损伤。

SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury.

机构信息

College of Life Science, Henan Normal University, Xinxiang, 453007, China.

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.

出版信息

Signal Transduct Target Ther. 2021 Dec 17;6(1):428. doi: 10.1038/s41392-021-00849-0.

DOI:10.1038/s41392-021-00849-0
PMID:34921131
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8677926/
Abstract

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.

摘要

SARS-CoV-2 感染引起的过度炎症与急性肺损伤和 COVID-19 严重程度有关。确定引发失控细胞因子血症的主要介质对于治疗至关重要。肥大细胞（MC）位于黏膜的战略性位置，可有益或有害地调节免疫炎症。在这项研究中，我们表明 SARS-CoV-2 触发的 MC 脱颗粒引发了肺泡上皮炎症和肺损伤。SARS-CoV-2 挑战诱导 ACE-2 人源化小鼠和恒河猴的 MC 脱颗粒，并且 Spike-RBD 与细胞中的 ACE2 结合可重现快速的 MC 脱颗粒；MC 脱颗粒改变了肺泡上皮细胞中的各种信号通路，特别是诱导促炎因子和随后破坏紧密连接。重要的是，临床 MC 稳定剂的给药可阻断脱颗粒，从而减轻 SARS-CoV-2 诱导的促炎因子产生并预防肺损伤。这些发现揭示了 SARS-CoV-2 引发肺炎症的新机制，并提示使用 MC 稳定剂作为 COVID-19 治疗的免疫调节剂的非适应证用途。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/a5d63a493f99/41392_2021_849_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/baa14a60cec3/41392_2021_849_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/54b84ce76a2d/41392_2021_849_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/55ebbca65bd7/41392_2021_849_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/b86782245ac5/41392_2021_849_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/b757aa61b9d5/41392_2021_849_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/6a4ff1e8ae0e/41392_2021_849_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/2a3f61144cb4/41392_2021_849_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/a5d63a493f99/41392_2021_849_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/baa14a60cec3/41392_2021_849_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/54b84ce76a2d/41392_2021_849_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/55ebbca65bd7/41392_2021_849_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/b86782245ac5/41392_2021_849_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/b757aa61b9d5/41392_2021_849_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/6a4ff1e8ae0e/41392_2021_849_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/2a3f61144cb4/41392_2021_849_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7e3/8683491/a5d63a493f99/41392_2021_849_Fig8_HTML.jpg

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