Intranasal administration of Acinetobacter lwoffii in a murine model of asthma induces IL-6-mediated protection associated with cecal microbiota changes

BackgroundEarly-life exposure to certain environmental bacteria including Acinetobacter lwoffii (AL) has been implicated in protection from chronic inflammatory diseases including asthma later in life. However, the underlying mechanisms at the immune-microbe interface remain largely unknown. MethodsThe effects of repeated intranasal AL exposure on local and systemic innate immune responses were investigated in wild-type and Il6(-/-), Il10(-/-), and Il17(-/-) mice exposed to ovalbumin-induced allergic airway inflammation. Those investigations were expanded by microbiome analyses. To assess for AL-associated changes in gene expression, the picture arising from animal data was supplemented by in vitro experiments of macrophage and T-cell responses, yielding expression and epigenetic data. ResultsThe asthma preventive effect of AL was confirmed in the lung. Repeated intranasal AL administration triggered a proinflammatory immune response particularly characterized by elevated levels of IL-6, and consequently, IL-6 induced IL-10 production in CD4(+) T-cells. Both IL-6 and IL-10, but not IL-17, were required for asthma protection. AL had a profound impact on the gene regulatory landscape of CD4(+) T-cells which could be largely recapitulated by recombinant IL-6. AL administration also induced marked changes in the gastrointestinal microbiome but not in the lung microbiome. By comparing the effects on the microbiota according to mouse genotype and AL-treatment status, we have identified microbial taxa that were associated with either disease protection or activity. ConclusionThese experiments provide a novel mechanism of Acinetobacter lwoffii-induced asthma protection operating through IL-6-mediated epigenetic activation of IL-10 production and with associated effects on the intestinal microbiome.

Automated summary

This research identifies a novel mechanism by which early-life exposure to Acinetobacter lwoffii (AL) can prevent chronic inflammatory diseases such as asthma. The study found that AL triggers a proinflammatory immune response characterized by elevated levels of IL-6 and subsequent IL-10 production in CD4(+) T-cells. This immune response, along with changes in the gastrointestinal microbiome, contribute to the protection against asthma.