Air pollution mediates diabetes by disrupting gut innate mucosal immunity

Abstract

Air pollution has emerged as an unexpected risk factor for diabetes1-6. The mechanisms linking air pollution and diabetes remain, however, unknown. It has been postulated that lung exposure mediates diabetes via systemic inflammation and insulin resistance7-9. By contrast, gut exposure to pollutants has received little attention, even though a large proportion of air pollution particles are swallowed after mucociliary clearance from the upper airways10. Here, we identified intestinal macrophages as key mediators linking air pollutants with impaired beta-cell function. Upon oral exposure to air pollution, intestinal macrophages up-regulated inflammatory- and interferon-response pathways, which disrupted their normal differentiation towards an anti-inflammatory/resident phenotype. The resulting pro-inflammatory milieu in the gut impaired beta-cell identity and function via local cytokine secretion from macrophages as genetic and pharmacological macrophage or IL-1{beta} ablation protected mice from developing air pollution-induced diabetes. These data establish intestinal macrophage-derived cytokines as key mediators of air pollution associated beta-cell dysfunction, thus pointing towards novel therapeutic strategies.