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

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 6; pp. 1186 - 1199.e7
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.06.2021; Elsevier Limited; Elsevier
• Subjects: Amphiregulin; Amphiregulin - pharmacology; Animals; Antibodies; Asthma; Biomarkers; Coronaviruses; COVID-19; Cytokines; Cytokines - metabolism; Disease Models, Animal; Disease Susceptibility; Host-Pathogen Interactions - immunology; Humans; IL-18; IL-6; Immunity, Cellular; Immunohistochemistry; Immunomodulation - drug effects; Infections; Inflammation; Inflammation Mediators - metabolism; Influenza; Influenza A virus - physiology; Innate immunity; Interleukin 18; Life Sciences; Lung - immunology; Lung - metabolism; Lung - pathology; Lung - virology; Lungs; Lymphocytes T; Mice; Mice, Transgenic; Morbidity; Mortality; Notch4; Pneumonia, Viral - etiology; Pneumonia, Viral - metabolism; Pneumonia, Viral - pathology; Public health; Receptor, Notch4 - antagonists & inhibitors; Receptor, Notch4 - genetics; Receptor, Notch4 - metabolism; regulatory T cells; Repair; Respiratory failure; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Severity of Illness Index; Signal Transduction; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tissues; Tumor necrosis factor-TNF; Viral diseases; Viral infections; Viruses; COVID-19; influenza; Notch4; regulatory T cells; amphiregulin; SARS-CoV-2; IL-18; IL-6
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2021.04.002

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. [Display omitted] •Notch4 expression on Treg cells is associated with COVID-19 disease severity•Notch4 inhibition suppresses lung inflammation in proxy viral mouse models•Notch4 limits amphiregulin-dependent lung Treg cell tissue repair functions Harb, Benamar, et al. find that interleukin-6 increases Notch4 expression on lung regulatory T cells, which, in turn, restrains production of the tissue repair cytokine amphiregulin and promotes severe lung inflammation. Their findings have implications for treatment of COVID-19 and other respiratory viral infections.