SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury.
Meng-Li WuFeng-Liang LiuJing SunXin LiXiao-Yan HeHong-Yi ZhengYan-Heng ZhouQihong YanLing ChenGuo-Ying YuJunbiao ChangXia JinJin-Cun ZhaoXin-Wen ChenYong-Tang ZhengJian-Hua WangPublished in: Signal transduction and targeted therapy (2021)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- oxidative stress
- diabetic rats
- high glucose
- induced apoptosis
- coronavirus disease
- type diabetes
- metabolic syndrome
- lipopolysaccharide induced
- blood brain barrier
- angiotensin converting enzyme
- skeletal muscle
- epithelial mesenchymal transition
- insulin resistance
- inflammatory response
- high fat diet induced
- endoplasmic reticulum stress
- cell death
- sensitive detection
- quantum dots