Nutrient-Sensing Ghrelin Receptor in Macrophages Modulates Bisphenol A-Induced Intestinal Inflammation in Mice.
Nutrient-Sensing Ghrelin Receptor in Macrophages Modulates Bisphenol A-Induced Intestinal Inflammation in Mice.
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DOI：
10.3390/genes14071455
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发表时间：
2023-07-16
期刊：
影响因子：
3.5
通讯作者：
Sun, Yuxiang
中科院分区：
文献类型：
--
作者：
Ye, Xiangcang;Liu, Zeyu;Han, Hye Won;Noh, Ji Yeon;Shen, Zheng;Kim, Da Mi;Wang, Hongying;Guo, Huiping;Ballard, Johnathan;Golovko, Andrei;Morpurgo, Benjamin;Sun, Yuxiang
双酚是具有内分泌干扰活性的环境毒素，但双酚A（BPA）及其类似物仍广泛用于制造塑料制品。有证据表明，BPA在人类和动物中引起炎症，但BPA的靶细胞类型尚未完全了解。在这项研究中，我们试图确定BPA对巨噬细胞的直接影响和BPA在小鼠肠道的免疫毒性。Ghrelin是一种重要的营养敏感激素，通过其受体生长激素促分泌素受体（GHSR）调节代谢和炎症。我们发现BPA促进肠道炎症，显示结肠中浸润的免疫细胞增加，结肠粘膜中Ghsr和促炎细胞因子和趋化因子如IL 6和CCl 2的表达增强。此外，我们发现，无论是长期和短期的BPA暴露升高促炎单核细胞和巨噬细胞在小鼠外周血单核细胞（PBMC）和腹腔巨噬细胞（PM），分别。为了确定GHSR在BPA介导的炎症中的作用，我们使用CRISPR基因编辑在小鼠巨噬细胞RAW264.7中产生了GhSR缺失突变。在野生型RAW264.7细胞中，BPA暴露促进巨噬细胞促炎性极化并增加Ghsr和细胞因子/趋化因子116和Ccl 2表达。有趣的是，Ghsr缺失突变体显示出响应BPA的促炎细胞因子/趋化因子表达的显著减少，表明GHSR是BPA诱导的促炎反应所需的。进一步了解营养感应GHSR信号如何调节BPA肠道免疫毒性，将有助于设计新的策略，以减轻BPA的免疫毒性，并为BPA的生物安全提供政策指导。
Bisphenols are environmental toxins with endocrine disruptor activity, yet bisphenol A (BPA) and its analogs are still widely used in manufacturing plastic products. There is evidence showing that BPA elicits inflammation in humans and animals, but the target cell types of BPA are not well understood. In this study, we sought to determine BPA’s direct effect on macrophages and BPA immunotoxicity in mouse intestine. Ghrelin is an important nutrient-sensing hormone, acting through its receptor growth hormone secretagogue receptor (GHSR) to regulate metabolism and inflammation. We found that BPA promotes intestinal inflammation, showing increased infiltrating immune cells in colons and enhanced expression of Ghsr and pro-inflammatory cytokines and chemokines, such as Il6 and Ccl2, in colonic mucosa. Moreover, we found that both long- and short-term BPA exposure elevated pro-inflammatory monocytes and macrophages in mouse peripheral blood mononuclear cells (PBMC) and peritoneal macrophages (PM), respectively. To determine the role of GHSR in BPA-mediated inflammation, we generated Ghsr deletion mutation in murine macrophage RAW264.7 using CRISPR gene editing. In wild-type RAW264.7 cells, the BPA exposure promotes macrophage pro-inflammatory polarization and increases Ghsr and cytokine/chemokine Il6 and Ccl2 expression. Interestingly, Ghsr deletion mutants showed a marked reduction in pro-inflammatory cytokine/chemokine expression in response to BPA, suggesting that GHSR is required for the BPA-induced pro-inflammatory response. Further understanding how nutrient-sensing GHSR signaling regulates BPA intestinal immunotoxicity will help design new strategies to mitigate BPA immunotoxicity and provide policy guidance for BPA biosafety.
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影响因子：
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