Published 2021
| Version v1
Publication
Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections
Creators
- Harb, Hani
- Benamar, Mehdi
- Lai, Peggy S
- Contini, Paola
- Griffith, Jason W
- Crestani, Elena
- Schmitz-Abe, Klaus
- Chen, Qian
- Fong, Jason
- Marri, Luca
- Filaci, Gilberto
- Del Zotto, Genny
- Pishesha, Novalia
- Kolifrath, Stephen
- Broggi, Achille
- Ghosh, Sreya
- Gelmez, Metin Yusuf
- Oktelik, Fatma Betul
- Cetin, Esin Aktas
- Kiykim, Ayca
- Kose, Murat
- Wang, Ziwei
- Cui, Ye
- Yu, Xu G
- Li, Jonathan Z
- Berra, Lorenzo
- Stephen-Victor, Emmanuel
- Charbonnier, Louis-Marie
- Zanoni, Ivan
- Ploegh, Hidde
- Deniz, Gunnur
- De Palma, Raffaele
- Chatila, Talal A
Contributors
Others:
- Harb, Hani
- Benamar, Mehdi
- Lai, Peggy S
- Contini, Paola
- Griffith, Jason W
- Crestani, Elena
- Schmitz-Abe, Klau
- Chen, Qian
- Fong, Jason
- Marri, Luca
- Filaci, Gilberto
- Del Zotto, Genny
- Pishesha, Novalia
- Kolifrath, Stephen
- Broggi, Achille
- Ghosh, Sreya
- Gelmez, Metin Yusuf
- Oktelik, Fatma Betul
- Cetin, Esin Akta
- Kiykim, Ayca
- Kose, Murat
- Wang, Ziwei
- Cui, Ye
- Yu, Xu G
- Li, Jonathan Z
- Berra, Lorenzo
- Stephen-Victor, Emmanuel
- Charbonnier, Louis-Marie
- Zanoni, Ivan
- Ploegh, Hidde
- Deniz, Gunnur
- De Palma, Raffaele
- Chatila, Talal A
Description
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.
Additional details
Identifiers
- URL
- http://hdl.handle.net/11567/1048939
- URN
- urn:oai:iris.unige.it:11567/1048939
Origin repository
- Origin repository
- UNIGE