Ivo Röwekamp (Berlin / DE), Laura Maschirow (Berlin / DE), Anne Rabes (Berlin / DE), Facundo Fiocca Vernengo (Berlin / DE), Sandra Caesar (Berlin / DE), Gitta Anne Heinz (Berlin / DE), Max Löhning (Berlin / DE), Mir-Farzin Mashreghi (Berlin / DE), Geraldine Nouailles (Berlin / DE), Norbert Suttorp (Berlin / DE), Sandra-Maria Wienhold (Berlin / DE), Ling Yao (Berlin / DE), Miha Milek (Berlin / DE), Anna Fagundes Fonseca (Berlin / DE), Dunja Bruder (Brunswick / DE), Martin Witzenrath (Berlin / DE), Julia D. Boehme (Brunswick / DE), Monika Puzianowska-Kuznicka (Warsaw / DE), Dieter Beule (Berlin / DE), Markus Heimesaat (Berlin / DE), Christoph S.N. Klose (Berlin / DE), Andreas Diefenbach (Berlin / DE), Bastian Opitz (Berlin / DE)
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 antibacterial defense was dependent on housing conditions of the mice, and mediated by the modulatory effect of IL-33 on the microbiota. Collectively, we provide insight into the bidirectional crosstalk between the innate immune system and the microbiota. We identify a mechanism, dependent on both genetic and environmental factors, that impacts the efficacy of antibacterial immune defense and thus susceptibility to pneumonia.