IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota.

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 <i>Streptococcus pneumoniae</i> lung infection than wild-type animals and that single-nucleotide polymorphisms in <i>IL33</i> and <i>IL1RL1</i> were associated with pneumococcal pneumonia in humans. The effect of IL-33 on <i>S. pneumoniae</i> 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.