Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections
| Autor: | Fatma Betul Oktelik, Qian Chen, Metin Yusuf Gelmez, Mehdi Benamar, Ayca Kiykim, Ye Cui, Jason Jun Hung Fong, Achille Broggi, Jonathan Z. Li, Sreya Ghosh, Peggy S. Lai, Hani Harb, Murat Kose, Esin Aktas Cetin, Paola Contini, Jason W. Griffith, Ivan Zanoni, Talal A. Chatila, Lorenzo Berra, Elena Crestani, Ziwei Wang, Novalia Pishesha, Klaus Schmitz-Abe, Louis-Marie Charbonnier, Raffaele De Palma, Günnur Deniz, Gilberto Filaci, Emmanuel Stephen-Victor, Stephen C. Kolifrath, Xu G. Yu, Luca Marri, Hidde L. Ploegh, Genny Del Zotto |
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| Přispěvatelé: | Boston Childrens Hosp, Division Immunology, Harvard Med Sch, Department pediatric, Massachusetts General Hospital, Div Pulm & Crit Care, Harvard Medical School - department medical, University Genoa, Dept Internal Medical, IRCCS Ospedale Policlinico San Martino [Genoa, Italy], IRCCS Istituto Giannina Gaslini [Genoa, Italy], Boston Childrens Hospital, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Istanbul Univ, Aziz Sancar Inst Expt Med Aziz Sancar DETAE, Istanbul Univ Cerrahpasa, Fac Med, Div Pediat Allergy & Immunol, Istanbul Univ, Fac Med, Dept Internal Med, Massachusetts Institute of Technology (MIT), Harvard Medical School [Boston] (HMS), DUMENIL, Anita |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Il-6 Survival [SDV]Life Sciences [q-bio] medicine.medical_treatment Severity of Illness Index T-Lymphocytes Regulatory regulatory T cells Mice 0302 clinical medicine Immunology and Allergy Receptor Notch4 Lung ComputingMilieux_MISCELLANEOUS Influenza-Virus Immunity Cellular Protection Immunohistochemistry [SDV] Life Sciences [q-bio] Infectious Diseases medicine.anatomical_structure Cytokine Influenza A virus 030220 oncology & carcinogenesis Host-Pathogen Interactions Cytokines Interleukin 18 Disease Susceptibility amphiregulin Inflammation Mediators medicine.symptom influenza IL-18 Signal Transduction Regulatory T cell Pneumonia Viral Immunology Activation Mice Transgenic Inflammation Biology Amphiregulin Article Virus Immunomodulation 03 medical and health sciences medicine Animals Humans Interleukin 6 IL-6 Innate immune system SARS-CoV-2 Notch4 Immunity COVID-19 Disease Models Animal 030104 developmental biology biology.protein Biomarkers |
| Zdroj: | Immunity Immunity, 2021, 54 (6), pp.1186-1199.e7. ⟨10.1016/j.immuni.2021.04.002⟩ |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2021.04.002 |
| Popis: | 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. Graphical abstract 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. |
| Databáze: | OpenAIRE |
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