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Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19

Author

Listed:
  • Ronja Mothes

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute)

  • Anna Pascual-Reguant

    (Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
    Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Ralf Koehler

    (Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute)

  • Juliane Liebeskind

    (Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
    Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Alina Liebheit

    (Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
    Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Sandy Bauherr

    (Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute)

  • Lars Philipsen

    (Otto-von-Guericke University Magdeburg
    Medical Faculty, Otto-von-Guericke-University Magdeburg)

  • Carsten Dittmayer

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Michael Laue

    (Robert Koch Institute)

  • Regina Manitius

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Sefer Elezkurtaj

    (Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Pawel Durek

    (Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute)

  • Frederik Heinrich

    (Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute)

  • Gitta A. Heinz

    (Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute)

  • Gabriela M. Guerra

    (Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute)

  • Benedikt Obermayer

    (Berlin Institute of Health at Charité-Universitätsmedizin Berlin)

  • Jenny Meinhardt

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Jana Ihlow

    (Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Josefine Radke

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    Berlin Institute of Health (BIH)
    Partner Site Berlin, CCCC (Campus Mitte)
    Universitätsmedizin Greifswald)

  • Frank L. Heppner

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    Cluster of Excellence, NeuroCure
    German Center for Neurodegenerative Diseases (DZNE) Berlin)

  • Philipp Enghard

    (Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin)

  • Helena Stockmann

    (Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin)

  • Tom Aschman

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Julia Schneider

    (Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin and German Centre for Infection Research)

  • Victor M. Corman

    (Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin and German Centre for Infection Research)

  • Leif E. Sander

    (Berlin Institute of Health (BIH)
    Charité-Universitätsmedizin Berlin and German Center for Lung Research (DZL))

  • Mir-Farzin Mashreghi

    (Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute)

  • Thomas Conrad

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Andreas C. Hocke

    (Charité-Universitätsmedizin Berlin and German Center for Lung Research (DZL))

  • Raluca A. Niesner

    (Freie Universität Berlin
    Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute)

  • Helena Radbruch

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Anja E. Hauser

    (Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
    Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

Abstract

Prolonged lung pathology has been associated with COVID-19, yet the cellular and molecular mechanisms behind this chronic inflammatory disease are poorly understood. In this study, we combine advanced imaging and spatial transcriptomics to shed light on the local immune response in severe COVID-19. We show that activated adventitial niches are crucial microenvironments contributing to the orchestration of prolonged lung immunopathology. Up-regulation of the chemokines CCL21 and CCL18 associates to endothelial-to-mesenchymal transition and tissue fibrosis within these niches. CCL21 over-expression additionally links to the local accumulation of T cells expressing the cognate receptor CCR7. These T cells are imprinted with an exhausted phenotype and form lymphoid aggregates that can organize in ectopic lymphoid structures. Our work proposes immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and perpetuates tissue remodeling.

Suggested Citation

  • Ronja Mothes & Anna Pascual-Reguant & Ralf Koehler & Juliane Liebeskind & Alina Liebheit & Sandy Bauherr & Lars Philipsen & Carsten Dittmayer & Michael Laue & Regina Manitius & Sefer Elezkurtaj & Pawe, 2023. "Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36333-2
    DOI: 10.1038/s41467-023-36333-2
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    References listed on IDEAS

    as
    1. Anna Pascual-Reguant & Ralf Köhler & Ronja Mothes & Sandy Bauherr & Daniela C. Hernández & Ralf Uecker & Karolin Holzwarth & Katja Kotsch & Maximilian Seidl & Lars Philipsen & Werner Müller & Chiara R, 2021. "Multiplexed histology analyses for the phenotypic and spatial characterization of human innate lymphoid cells," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
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