SARS-CoV-2 spike spurs intestinal inflammation via VEGF production in enterocytes.
SARS-CoV-2 spike spurs intestinal inflammation via VEGF production in enterocytes.
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SARS-CoV-2 刺突通过肠上皮细胞中 VEGF 的产生刺激肠道炎症
DOI：
10.15252/emmm.202114844
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发表时间：
2022-05-09
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
严重急性呼吸综合征冠状病毒-2（SARS-CoV-2）可引起胃肠道（GI）症状，这些症状通常与COVID-19的严重程度相关。在这里，我们探讨了COVID-19肠道炎症的发病机制。血浆VEGF水平在有胃肠道症状的患者中尤其升高，并与肠水肿和疾病进展显著相关。通过模拟SARS-CoV-2刺突蛋白刺激后肠道炎症的动物模型，我们进一步揭示了VEGF在循环中上升之前在十二指肠中过度产生。从机制上讲，SARS-CoV-2刺突通过激活肠上皮细胞（但不是内皮细胞）中的Ras-Raf-MEK-ERK信号传导并诱导渗透性和炎症来促进VEGF的产生。阻断ERK/VEGF轴能够挽救血管通透性，减轻体内肠道炎症。这些发现为COVID-19的胃肠道症状提供了机制解释和治疗靶点。VEGF是血管通透性和炎症的关键因素。VEGF与COVID-19相关GI症状之间的相关性已经确立：在病毒刺突蛋白诱导的ERK激活后，肠细胞产生VEGF，导致肠道发炎和渗漏。
Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) can cause gastrointestinal (GI) symptoms that often correlate with the severity of COVID‐19. Here, we explored the pathogenesis underlying the intestinal inflammation in COVID‐19. Plasma VEGF level was particularly elevated in patients with GI symptoms and significantly correlated with intestinal edema and disease progression. Through an animal model mimicking intestinal inflammation upon stimulation with SARS‐CoV‐2 spike protein, we further revealed that VEGF was over‐produced in the duodenum prior to its ascent in the circulation. Mechanistically, SARS‐CoV‐2 spike promoted VEGF production through activating the Ras‐Raf‐MEK‐ERK signaling in enterocytes, but not in endothelium, and inducing permeability and inflammation. Blockage of the ERK/VEGF axis was able to rescue vascular permeability and alleviate intestinal inflammation in vivo. These findings provide a mechanistic explanation and therapeutic targets for the GI symptoms of COVID‐19. VEGF is a key factor in vascular permeability and inflammation. A correlation between VEGF and COVID‐19‐related GI symptoms was established: upon viral spike protein‐induced ERK activation, VEGF was produced by the enterocytes, which led to inflamed and leaky gut.
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