We previously found that air pollution particles reaching the gastrointestinal tract elicit gut inflammation as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. This inflammatory response was associated with beta-cell dysfunction and glucose intolerance. So far, it remains unclear whether gut inflammatory changes upon oral air pollution exposure are causally linked to the development of diabetes. Hence, our aim was to assess the role of immune cells in mediating glucose intolerance instigated by orally administered air pollutants. To assess immune-mediated mechanisms underlying air pollution-induced glucose intolerance, we administered diesel exhaust particles (DEP; NIST 1650b, 12 µg five days/week) or phosphate-buffered saline (PBS) via gavage for up to 10 months to wild-type mice and mice with genetic or pharmacological depletion of innate or adaptive immune cells. We performed unbiased RNA-sequencing of intestinal macrophages to elucidate signaling pathways that could be pharmacologically targeted and applied an in vitro approach to confirm these pathways. Oral exposure to air pollution particles induced an interferon and inflammatory signature in colon macrophages together with a decrease of CCR2− anti-inflammatory/resident macrophages. Depletion of macrophages, NLRP3 or IL-1β protected mice from air pollution-induced glucose intolerance. On the contrary, Rag2-/- mice lacking adaptive immune cells developed pronounced gut inflammation and glucose intolerance upon oral DEP exposure. In mice, oral exposure to air pollution particles triggers an immune-mediated response in intestinal macrophages that contributes to the development of a diabetes-like phenotype. These findings point towards new pharmacologic targets in diabetes instigated by air pollution particles.

中文翻译：

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柴油机尾气颗粒 (DEP) 诱导的葡萄糖耐受不良是由小鼠肠道先天免疫反应和 NLRP3 激活驱动的

我们之前发现，到达胃肠道的空气污染颗粒会引发肠道炎症，促炎细胞因子和单核细胞/巨噬细胞标记物的基因表达上调表明了这一点。这种炎症反应与β细胞功能障碍和葡萄糖耐受不良有关。到目前为止，尚不清楚口腔空气污染暴露引起的肠道炎症变化是否与糖尿病的发生存在因果关系。因此，我们的目的是评估免疫细胞在介导口服空气污染物引起的葡萄糖不耐受中的作用。为了评估空气污染引起的葡萄糖不耐受的免疫介导机制，我们施用了柴油机尾气颗粒（DEP；NIST 1650b，12 µg，五天/周）或磷酸盐缓冲盐水（PBS），通过强饲法给野生型小鼠和先天性或适应性免疫细胞遗传或药理学耗竭的小鼠长达 10 个月。我们对肠道巨噬细胞进行了无偏倚的 RNA 测序，以阐明可药理学靶向的信号通路，并应用体外方法来确认这些通路。口腔暴露于空气污染颗粒会诱导结肠巨噬细胞中的干扰素和炎症特征，同时 CCR2− 抗炎/常驻巨噬细胞减少。巨噬细胞、NLRP3 或 IL-1β 的消耗可以保护小鼠免受空气污染引起的葡萄糖不耐受。相反，缺乏适应性免疫细胞的 Rag2-/- 小鼠在口服 DEP 暴露后出现明显的肠道炎症和葡萄糖不耐受。在小鼠中，口腔接触空气污染颗粒会引发肠道巨噬细胞的免疫介导反应，从而导致糖尿病样表型的发展。这些发现指出了空气污染颗粒引发的糖尿病的新药理学靶点。