tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Mehdi Benamar[SUP] 1 [/SUP], Peggy S Lai[SUP] 2 [/SUP], Paola Contini[SUP] 3 [/SUP], Jason W Griffith[SUP] 2 [/SUP], Elena Crestani[SUP] 1 [/SUP], Klaus Schmitz-Abe[SUP] 1 [/SUP], Qian Chen[SUP] 1 [/SUP], Jason Fong[SUP] 1 [/SUP], Luca Marri[SUP] 4 [/SUP], Gilberto Filaci[SUP] 5 [/SUP], Genny Del Zotto[SUP] 6 [/SUP], Novalia Pishesha[SUP] 7 [/SUP], Stephen Kolifrath[SUP] 7 [/SUP], Achille Broggi[SUP] 1 [/SUP], Sreya Ghosh[SUP] 1 [/SUP], Metin Yusuf Gelmez[SUP] 8 [/SUP], Fatma Betul Oktelik[SUP] 8 [/SUP], Esin Aktas Cetin[SUP] 8 [/SUP], Ayca Kiykim[SUP] 9 [/SUP], Murat Kose[SUP] 10 [/SUP], Ziwei Wang[SUP] 1 [/SUP], Ye Cui[SUP] 1 [/SUP], Xu G Yu[SUP] 11 [/SUP], Jonathan Z Li[SUP] 12 [/SUP], Lorenzo Berra[SUP] 13 [/SUP], Emmanuel Stephen-Victor[SUP] 1 [/SUP], Louis-Marie Charbonnier[SUP] 1 [/SUP], Ivan Zanoni[SUP] 1 [/SUP], Hidde Ploegh[SUP] 7 [/SUP], Gunnur Deniz[SUP] 8 [/SUP], Raffaele De Palma[SUP] 14 [/SUP], Talal A Chatila[SUP] 15 [/SUP]
Affiliations
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.
. 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[SUP] 1 [/SUP], Mehdi Benamar[SUP] 1 [/SUP], Peggy S Lai[SUP] 2 [/SUP], Paola Contini[SUP] 3 [/SUP], Jason W Griffith[SUP] 2 [/SUP], Elena Crestani[SUP] 1 [/SUP], Klaus Schmitz-Abe[SUP] 1 [/SUP], Qian Chen[SUP] 1 [/SUP], Jason Fong[SUP] 1 [/SUP], Luca Marri[SUP] 4 [/SUP], Gilberto Filaci[SUP] 5 [/SUP], Genny Del Zotto[SUP] 6 [/SUP], Novalia Pishesha[SUP] 7 [/SUP], Stephen Kolifrath[SUP] 7 [/SUP], Achille Broggi[SUP] 1 [/SUP], Sreya Ghosh[SUP] 1 [/SUP], Metin Yusuf Gelmez[SUP] 8 [/SUP], Fatma Betul Oktelik[SUP] 8 [/SUP], Esin Aktas Cetin[SUP] 8 [/SUP], Ayca Kiykim[SUP] 9 [/SUP], Murat Kose[SUP] 10 [/SUP], Ziwei Wang[SUP] 1 [/SUP], Ye Cui[SUP] 1 [/SUP], Xu G Yu[SUP] 11 [/SUP], Jonathan Z Li[SUP] 12 [/SUP], Lorenzo Berra[SUP] 13 [/SUP], Emmanuel Stephen-Victor[SUP] 1 [/SUP], Louis-Marie Charbonnier[SUP] 1 [/SUP], Ivan Zanoni[SUP] 1 [/SUP], Hidde Ploegh[SUP] 7 [/SUP], Gunnur Deniz[SUP] 8 [/SUP], Raffaele De Palma[SUP] 14 [/SUP], Talal A Chatila[SUP] 15 [/SUP]
Affiliations
- PMID: 33915108
- PMCID: PMC8080416
- DOI: 10.1016/j.immuni.2021.04.002
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.