小柯机器人

美国哈佛医学院Talal A. Chatila研究组发现，Notch4信号限制调节性T细胞介导的组织修复并促进病毒感染中的严重肺部炎症。相关论文于2021年4月28日在线发表于国际学术期刊《免疫》。

在多国家COVID-19患者队列中，研究人员发现循环调节性T（Treg）细胞上Notch4表达的增加与疾病的严重程度、预计的死亡率以及康复后的下降有关。在传统和人源化小鼠中，Treg细胞中Notch4的缺失或抗Notch4抗体的治疗使病毒RNA的合成类似物或H1N1流感病毒的合成类似物诱导的先天免疫功能失调，并挽救了疾病的发病率和死亡率。

从机制上讲，Notch4抑制白介素18的介导白细胞介素18的诱导，这是组织修复所必需的细胞因子。Notch4抑制的保护作用通过双调蛋白的治疗得以重现，相反，其拮抗作用也被消除。COVID-19受试者的双调蛋白下降与疾病严重程度和Notch4表达有关。因此，Treg细胞上的Notch4表达可动态抑制双调蛋白依赖性组织修复，从而促进严重的肺部炎症，对COVID-19和相关感染具有治疗意义。

附：英文原文

Title: Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections

Author: Hani Harb, Mehdi Benamar, Peggy S. Lai, Paola Contini, Jason W. Griffith, Elena Crestani, Klaus Schmitz-Abe, Qian Chen, Jason Fong, Luca Marri, Gilberto Filaci, Genny Del Zotto, Novalia Pishesha, Stephen Kolifrath, Achille Broggi, Sreya Ghosh, Metin Yusuf Gelmez, Fatma Betul Oktelik, Esin Aktas Cetin, Ayca Kiykim, Murat Kose, Ziwei Wang, Ye Cui, Xu G. Yu, Jonathan Z. Li, Lorenzo Berra, Emmanuel Stephen-Victor, Louis-Marie Charbonnier, Ivan Zanoni, Hidde Ploegh, Gunnur Deniz, Raffaele De Palma, Talal A. Chatila

Issue&Volume: 2021-04-28

Abstract: A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In aprospective multi-country cohort of COVID-19 patients, we found that increased Notch4expression on circulating regulatory T (Treg) cells was associated with disease severity,predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanizedmice normalized the dysregulated innate immunity and rescued disease morbidity andmortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically,Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessaryfor tissue repair. Protection by Notch4 inhibition was recapitulated by therapy withAmphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declinedin COVID-19 subjects as a function of disease severity and Notch4 expression. Thus,Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissuerepair to promote severe lung inflammation, with therapeutic implications for COVID-19and related infections.

DOI: 10.1016/j.immuni.2021.04.002

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00139-4

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