IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota
Ivo Röwekamp, Laura Maschirow, Anne Rabes, Facundo Fiocca Vernengo, Lutz Hamann, Gitta Anne Heinz, Mir‐Farzin Mashreghi, Sandra Caesar, Miha Milek, Alexandra Muniz Gomes da Fonseca, Sandra-Maria Wienhold, Geraldine Nouailles, Ling Yao, Soraya Mousavi, Dunja Bruder, Julia D. Boehme, Monika Puzianowska‐Kuźnicka, Dieter Beule, Martin Witzenrath, CAPNETZ Study Group, Max Löhning, Christoph S. N. Klose, Markus M. Heimesaat, Andreas Diefenbach, Bastian Opitz, André Fuchs, Maximilian Engelmann, Gregor Paul, Mousa Ayoub, Katharina Groehl, Katrin Riedl, Daiana Stolz, Wolfgang Bauer, Eva Diehl-Wiesenecker, Iris von Wunsch-Rolshoven Terue, Noah Galtung, Norbert Suttorp, Martin Witzenrath, Christian Wildberg, Caitlin Pley, Enrico Zessin, Sibylle Schmager, Bernhard Schaaf, Julius Kremling, Daniela Nickoleit-Bitzenberger, Harun Azzaui, Martin Hower, Frederik Hempel, Katharina Prebeg, Kalina Popkirova, Martin Kolditz, B. Schulte‐Hubbert, Simona Langner, Gernot Rohde, Carla Bellinghausen, Achim Grϋnewaldt, Adrian Endres, Carlo Sala Frigerio, Benno Fiedler, Marcus Panning, Tobias Welte, Isabell Pink, Nora Drick, Thomas Fϋhner, Mariet van’t Klooster, T H Steinberg, Grit Barten-Neiner, W. Kröner, Olesya Unruh, Nina Adaskina, Frank Eberhardt, Christina Julius, Thomas Illig, Norman Klopp, Mathias W. Pletz, Benjamin T. Schleenvoigt, Christina Bahrs, Anne Moeser, Juliane Ankert, Urte Sommerwerck, T Wintermantel, Daniel Drömann, P. Parschke, Klaas Franzen, Jan Rupp, Frederike Waldeck, Nadja Käding, Christoph D. Spinner, Johanna Erber, Florian Voit, Jochen Schneider, Marco Falcone, Giusy Tiseo, David F. Heigener, I. Hering, Werner C. Albrich, Frank Rassouli, Benjamin Wirth, Claus Neurohr, Andreas Essig
Abstract
IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals and that single-nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production in innate lymphoid cells (ILCs) but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33’s influence on IL-22-dependent antibacterial defense was dependent on housing conditions of the mice and mediated by IL-33’s modulatory effect on the gut microbiota. Collectively, we provide insight into the bidirectional crosstalk between the innate immune system and the microbiota. We conclude that both genetic and environmental factors influence the gut microbiota, thereby impacting the efficacy of antibacterial immune defense and susceptibility to pneumonia.