IL-33 modulates IL-22-dependent antibacterial defence by regulating the microbiota
RÖWEKAMP I. 1, MASCHIROW L. 1, RABES A. 1, FIOCCA VERNENGO F. 1, HAMANN L. 2, HEINZ G. 5, MASHREGHI M. 5, CAESAR S. 1, FAGUNDES A. 2, WIENHOLD S. 1, NOUAILLES-KURSAR G. 1, YAO L. 1, SANDER L. 1, WITZENRATH M. 1,4, LÖHNING M. 5, HEIMESAAT M. 2, KLOSE C. 2, DIEFENBACH A. 2, OPITZ B. 1,4
1 Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 2 Institute of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 3 Core Unit Bioinformatics, Berlin Institute of Health at Charité, Berlin, Germany; 4 German center for lung research (DZL), Berlin, Germany; 5 German Rheumatism Research Center, a Leibniz Institute, Berlin, Germany
IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated during bacterial infection is incompletely understood. Here, we show that mice lacking IL-33 or its receptor were more susceptible to Streptococcus pneumoniae lung infection than wild-type controls, 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, but independent of type 2 innate lymphoid cells (ILCs), IL-4 and IL-13. Instead, IL-33´s influence on antibacterial defense was directly dependent on its effect on the intestinal microbiota. Collectively, our findings provide insight into the bidirectional crosstalk between the innate immune system and the microbiota and how it shapes susceptibility to bacterial infection.