IL-13 is a driver of COVID-19 severity.
IL-13 is a driver of COVID-19 severity.
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DOI：
10.1172/jci.insight.150107
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发表时间：
2021-08-09
期刊：
影响因子：
8
通讯作者：
Petri WA Jr
中科院分区：
文献类型：
--
作者：
Donlan AN;Sutherland TE;Marie C;Preissner S;Bradley BT;Carpenter RM;Sturek JM;Ma JZ;Moreau GB;Donowitz JR;Buck GA;Serrano MG;Burgess SL;Abhyankar MM;Mura C;Bourne PE;Preissner R;Young MK;Lyons GR;Loomba JJ;Ratcliffe SJ;Poulter MD;Mathers AJ;Day AJ;Mann BJ;Allen JE;Petri WA Jr
免疫失调是SARS-CoV-2感染较严重阶段的特征。了解免疫系统导致COVID-19严重程度的机制可能会开辟新的治疗途径。在这里，我们报告了IL-13升高与2个独立患者队列的机械通气需求相关。此外，在接受Dupilumab（一种阻断IL-13和IL-4信号传导的mAb）治疗时获得COVID-19的患者病情较轻。在SARS-CoV-2感染的小鼠中，IL-13中和作用降低了死亡和疾病严重程度，而不影响病毒载量，证明了这种细胞因子的免疫致病作用。抗IL-13治疗感染小鼠后，透明质酸合成酶1（Has 1）是下调最多的基因，肺中透明质酸（HA）多糖的积累减少。在COVID-19患者中，肺和血浆中的HA增加。阻断HA受体CD 44可降低感染小鼠的死亡率，支持HA作为致病介质的重要性。最后，通过给予IL-13在小鼠肺中直接诱导HA，表明IL-13在肺部疾病中的新作用。了解IL-13和HA的作用对COVID-19的治疗以及潜在的其他肺部疾病具有重要意义。严重COVID-19患者的IL-13水平升高。在该疾病的小鼠模型中，IL-13中和减轻了疾病并减少了肺部HA沉积。在肺中施用IL-13诱导的HA。HA受体CD 44的阻断可预防死亡，这突出了肺病理学中IL-13介导的HA合成的潜在新机制。
Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2–infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti–IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13–induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13–mediated HA synthesis in pulmonary pathology.
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