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

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Immunity


. 2021 Apr 22;S1074-7613(21)00139-4.
doi: 10.1016/j.immuni.2021.04.002. Online ahead of print.
Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections


Hani Harb ¹ , Mehdi Benamar ¹ , Peggy S Lai ² , Paola Contini ³ , Jason W Griffith ² , Elena Crestani ¹ , Klaus Schmitz-Abe ¹ , Qian Chen ¹ , Jason Fong ¹ , Luca Marri ⁴ , Gilberto Filaci ⁵ , Genny Del Zotto ⁶ , Novalia Pishesha ⁷ , Stephen Kolifrath ⁷ , Achille Broggi ¹ , Sreya Ghosh ¹ , Metin Yusuf Gelmez ⁸ , Fatma Betul Oktelik ⁸ , Esin Aktas Cetin ⁸ , Ayca Kiykim ⁹ , Murat Kose ¹⁰ , Ziwei Wang ¹ , Ye Cui ¹ , Xu G Yu ¹¹ , Jonathan Z Li ¹² , Lorenzo Berra ¹³ , Emmanuel Stephen-Victor ¹ , Louis-Marie Charbonnier ¹ , Ivan Zanoni ¹ , Hidde Ploegh ⁷ , Gunnur Deniz ⁸ , Raffaele De Palma ¹⁴ , Talal A Chatila ¹⁵



Affiliations

• PMID: 33915108
• PMCID: PMC8080416
• DOI: 10.1016/j.immuni.2021.04.002

Free PMC article

Abstract

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression 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 humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality 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 necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.

Keywords: COVID-19; IL-18; IL-6; Notch4; SARS-CoV-2; amphiregulin; influenza; regulatory T cells.