MicroRNA-223 Dampens Pulmonary Inflammation during Pneumococcal Pneumonia
Cengiz Goekeri,
Peter Pennitz,
Wibke Groenewald,
Ulrike Behrendt,
Holger Kirsten,
Christian M. Zobel,
Sarah Berger,
Gitta A. Heinz,
Mir-Farzin Mashreghi,
Sandra-Maria Wienhold,
Kristina Dietert,
Anca Dorhoi,
Achim D. Gruber,
Markus Scholz,
Gernot Rohde,
Norbert Suttorp,
CAPNETZ Study Group,
Martin Witzenrath,
Geraldine Nouailles
Affiliations
Cengiz Goekeri
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Peter Pennitz
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Wibke Groenewald
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Ulrike Behrendt
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Holger Kirsten
Institute for Medical Informatics, Statistics, and Epidemiology, Universität Leipzig, 04107 Leipzig, Germany
Christian M. Zobel
Department of Internal Medicine, Bundeswehrkrankenhaus Berlin, 10115 Berlin, Germany
Sarah Berger
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Gitta A. Heinz
Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), ein Institut der Leibniz-Gemeinschaft, 10117 Berlin, Germany
Mir-Farzin Mashreghi
Therapeutic Gene Regulation, Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), ein Institut der Leibniz-Gemeinschaft, 10117 Berlin, Germany
Sandra-Maria Wienhold
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Kristina Dietert
Institute of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany
Anca Dorhoi
Institute of Immunology, Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany
Achim D. Gruber
Institute of Veterinary Pathology, Freie Universität Berlin, 14163 Berlin, Germany
Markus Scholz
Institute for Medical Informatics, Statistics, and Epidemiology, Universität Leipzig, 04107 Leipzig, Germany
Gernot Rohde
Department of Respiratory Medicine, Medical Clinic I, Goethe-Universität Frankfurt am Main, 60596 Frankfurt am Main, Germany
Norbert Suttorp
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
CAPNETZ Study Group
CAPNETZ STIFTUNG, 30625 Hannover, Germany
Martin Witzenrath
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Geraldine Nouailles
Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Community-acquired pneumonia remains a major contributor to global communicable disease-mediated mortality. Neutrophils play a leading role in trying to contain bacterial lung infection, but they also drive detrimental pulmonary inflammation, when dysregulated. Here we aimed at understanding the role of microRNA-223 in orchestrating pulmonary inflammation during pneumococcal pneumonia. Serum microRNA-223 was measured in patients with pneumococcal pneumonia and in healthy subjects. Pulmonary inflammation in wild-type and microRNA-223-knockout mice was assessed in terms of disease course, histopathology, cellular recruitment and evaluation of inflammatory protein and gene signatures following pneumococcal infection. Low levels of serum microRNA-223 correlated with increased disease severity in pneumococcal pneumonia patients. Prolonged neutrophilic influx into the lungs and alveolar spaces was detected in pneumococci-infected microRNA-223-knockout mice, possibly accounting for aggravated histopathology and acute lung injury. Expression of microRNA-223 in wild-type mice was induced by pneumococcal infection in a time-dependent manner in whole lungs and lung neutrophils. Single-cell transcriptome analyses of murine lungs revealed a unique profile of antimicrobial and cellular maturation genes that are dysregulated in neutrophils lacking microRNA-223. Taken together, low levels of microRNA-223 in human pneumonia patient serum were associated with increased disease severity, whilst its absence provoked dysregulation of the neutrophil transcriptome in murine pneumococcal pneumonia.
