长COVID (PASC)通过自我维持的促炎TLR4/RAGE环S100A8/A9 > TLR4/RAGE信号传导,诱导IL-1b、IL-6和TNFa的慢性表达:抗炎Ezrin肽的潜在治疗方法

R. Holms
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引用次数: 18

摘要

长冠状病毒病,也被称为COVID急性后后遗症(PASC),可能是在SARS-CoV-2感染和急性COVID-19期间由SARS-CoV-2刺状蛋白结合和细胞膜表达的晚期糖基化终产物受体(mRAGE)和toll样受体4 (TLR4)超激活触发的。SARS-CoV-2通过刺突结合mRAGE(不是ACE2)感染肺单核细胞。在急性COVID-19期间,高水平的IL-6过度刺激S100A8/A9的表达和分泌。虽然在一半的长冠状病毒(PASC)患者中检测不到病毒蛋白或mRNA,但血清IL-1b、IL-6、TNFa和S100A8/A9水平显著升高。急性COVID-19期间建立了病理性促炎反馈回路(TLR4/RAGE-loop),该回路由S100A8/A9 > RAGE/TLR4慢性炎症信号维持,即使在SARS-CoV-2被清除后也是如此。在长型COVID/PASC期间,Ca2+结合蛋白S100A8/A9慢性刺激TLR4/ rage信号传导,诱导IL-1b、IL-6和TNFa的慢性表达。分泌的IL-6与其他细胞表面的IL-6R受体结合,并通过STAT3和C/EBPb发出信号,更多地表达S100A8/A9。分泌的IL-1b与其他细胞上的受体IL-1R结合,并通过NFkB发出信号,更多地表达mRAGE和TLR4。新的S100A8/A9可以结合并激活细胞表面mRAGE和TLR4,刺激更多IL-1b、IL-6和TNFa的表达。该过程建立了一个致病性促炎TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6,产生多器官炎症,持续存在于血管、大脑、肝脏、心脏、肾脏、肠道和肌肉骨骼系统,并负责与长COVID/PASC相关的所有复杂病理。IL-1、IL-6和TNFa的慢性表达对于TLR4/RAGE-loop的维持和COVID/PASC的长期持续至关重要。Ezrin肽是IL-1、IL-6、IL-8和TNFa表达的抑制剂,因此目前正在研究作为长期COVID/PASC的潜在治疗方法。有初步的轶事证据表明,在接受ezrin肽治疗后,一些长期感染COVID/PASC的患者志愿者的症状有所缓解(尚未得到正式临床试验的证实)。
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Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy
Long COVID, also referred to as Post-Acute Sequelae of COVID (PASC), is probably triggered during SARS-CoV-2 infection and acute COVID-19 by SARS-CoV-2 Spike-protein binding and hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) and Toll-Like Receptor 4 (TLR4). SARS-CoV-2 infects lung monocytes by Spike binding to mRAGE (not ACE2). During acute COVID-19, high levels of IL-6 hyper-stimulate S100A8/A9 expression and secretion. Although no viral protein nor mRNA can be detected in half of long COVID (PASC) patients, there is a significant elevation of serum levels of IL-1b, IL-6, TNFa, and S100A8/A9. It appears that a pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) is established during acute COVID-19, which is maintained by S100A8/A9 > RAGE/TLR4 chronic inflammatory signalling, even after SARS-CoV-2 has been cleared from the body. During long COVID/PASC, Ca2+-binding protein S100A8/A9 chronically stimulates TLR4/RAGE-signalling to induce chronic expression of IL-1b, IL-6 and TNFa. Secreted IL-6 binds to its IL-6R receptor on the surface of other cells and signals via STAT3 and C/EBPb for more S100A8/A9 expression. Secreted IL-1b binds to its receptor IL-1R on other cells, and signals via NFkB for more mRAGE and TLR4 expression. New S100A8/A9 can bind and activate cell-surface mRAGE and TLR4 to stimulate expression of more IL-1b, IL-6 and TNFa. This process establishes a pathogenic pro-inflammatory TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6, which generates multi-organ inflammation that persists in the blood vessels, the brain, the liver, the heart, the kidneys, the gut and the musculo-skeletal system, and is responsible for all the complex pathologies associated with long COVID/PASC. Chronic expression of IL-1, IL-6 and TNFa is critical for the maintenance of the TLR4/RAGE-loop and persistence of long COVID/PASC. Ezrin peptides are inhibitors of IL-1, IL-6, IL-8 and TNFa expression, so are now being investigated as potential therapy for long COVID/PASC. There is preliminary anecdotal evidence of symptomatic relief (not confirmed yet by formal clinical trials) from a few long COVID/PASC patient volunteers, after treatment with ezrin peptide therapy.
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Immuno-Analyse & Biologie Specialisee
Immuno-Analyse & Biologie Specialisee 医学-医学实验技术
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