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

H Harb, M Benamar, PS Lai, P Contini, JW Griffith… - Immunity, 2021 - cell.com
H Harb, M Benamar, PS Lai, P Contini, JW Griffith, E Crestani, K Schmitz-Abe, Q Chen
Immunity, 2021cell.com
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 …
Summary
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.
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