2. Academic Validation
  3. Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections

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

  • Immunity. 2021 Jun 8;54(6):1186-1199.e7. doi: 10.1016/j.immuni.2021.04.002.
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

Affiliations

  • 1 Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • 2 Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 3 Deptartment of Internal Medicine, University of Genoa, Genoa, Italy; Unit of Clinical Immunology and Translational Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
  • 4 Unit of Clinical Immunology and Translational Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
  • 5 Biotherapy Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
  • 6 Department of Research and Diagnostics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • 7 Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
  • 8 Department of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkey.
  • 9 Division of Pediatric Allergy and Immunology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
  • 10 Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey.
  • 11 Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard Medical School, Boston, MA, USA.
  • 12 Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 13 Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 14 Deptartment of Internal Medicine, University of Genoa, Genoa, Italy; Unit of Clinical Immunology and Translational Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; CNR-Institute of Biomolecular Chemistry (IBC), Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
  • 15 Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Electronic address: talal.chatila@childrens.harvard.edu.
PMID: 33915108 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z