The interleukin-33 receptor contributes to pulmonary responses to ozone in male mice: role of the microbiome

被引:20
作者
Kasahara, David I. [1 ]
Wilkinson, Jeremy E. [2 ]
Cho, Youngji [1 ]
Cardoso, Aline P. [1 ]
Huttenhower, Curtis [2 ]
Shore, Stephanie A. [1 ]
机构
[1] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Mol & Integrat Physiol Sci Program, 665 Huntington Av Bld1 Room 319, Boston, MA 02115 USA
[2] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 665 Huntington Ave, Huntington, MA 02115 USA
关键词
IL-33; Sex differences; Airway responsiveness; Neutrophil; Interleukin-5; INDUCED AIRWAY HYPERRESPONSIVENESS; INNATE LYMPHOID-CELLS; GUT MICROBIOTA; BRONCHIAL REACTIVITY; SEX-DIFFERENCES; IL-33; INFLAMMATION; ASTHMA; HYPERREACTIVITY; LACTOBACILLUS;
D O I
10.1186/s12931-019-1168-x
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
BackgroundInterleukin-33 is released in the airways following acute ozone exposure and has the ability to cause airway hyperresponsiveness, a defining feature of asthma. Ozone causes greater airway hyperresponsiveness in male than female mice. Moreover, sex differences in the gut microbiome account for sex differences in this response to ozone. The purpose of this study was to determine whether there were sex differences in the role of interleukin-33 in ozone-induced airway hyperresponsiveness and to examine the role of the microbiome in these events.MethodsWildtype mice and mice genetically deficient in ST2, the interleukin-33 receptor, were housed from weaning with either other mice of the same genotype and sex, or with mice of the same sex but opposite genotype. At 15weeks of age, fecal pellets were harvested for 16S rRNA sequencing and the mice were then exposed to air or ozone. Airway responsiveness was measured and a bronchoalveolar lavage was performed 24h after exposure.ResultsIn same-housed mice, ozone-induced airway hyperresponsiveness was greater in male than female wildtype mice. ST2 deficiency reduced ozone-induced airway hyperresponsiveness in male but not female mice and abolished sex differences in the response to ozone. However, sex differences in the role of interleukin-33 were unrelated to type 2 cytokine release: ozone-induced increases in bronchoalveolar lavage interleukin-5 were greater in females than males and ST2 deficiency virtually abolished interleukin-5 in both sexes. Since gut microbiota contribute to sex differences in ozone-induced airway hyperresponsiveness, we examined the role of the microbiome in these ST2-dependent sex differences. To do so, we cohoused wildtype and ST2 deficient mice, a situation that allows for transfer of microbiota among cage-mates. Cohousing altered the gut microbial community structure, as indicated by 16S rRNA gene sequencing of fecal DNA and reversed the effect of ST2 deficiency on pulmonary responses to ozone in male mice.ConclusionsThe data indicate that the interleukin-33 /ST2 pathway contributes to ozone-induced airway hyperresponsiveness in male mice and suggest that the role of interleukin-33 is mediated at the level of the gut microbiome.
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页数:15
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