Department of Molecular Genetics, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands.
Department of Surgery, School of Nutrition & Translational Research Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands.
J Pathol. 2020 Aug;251(4):429-439. doi: 10.1002/path.5477. Epub 2020 Jul 7.
Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1 ) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17β-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1 mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1 mice in contrast to male Npc1 mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
尽管人们越来越意识到男性和女性之间炎症反应的差异，但只有有限的研究关注这些性别差异背后的生物学因素。胆固醇衍生物 27-羟胆固醇（27HC）已在使用动脉粥样硬化和非酒精性脂肪性肝炎（NASH）的小鼠模型的独立实验中显示出相反的炎症作用，这些病理学特征是由胆固醇引起的炎症。由于这些体内模型中使用的小鼠的性别不同，我们假设 27HC 在雄性中表现出与雌性相反的炎症作用。为了探索 27HC 在人类中的抗炎作用是否存在性别差异，我们测量了肥胖个体的血浆 27HC 水平，并将其与肝炎症参数相关联。为了研究 27HC 是否对炎症产生性别相反的作用，我们将 27HC 注射到尼曼-匹克病 C1 型（Npc1）小鼠中，该小鼠被用作胆固醇诱导炎症的极端模型。最后，我们研究了雌激素信号转导在骨髓来源的巨噬细胞（BMDM）中对该机制的作用，这些巨噬细胞用 27HC 和 17β-雌二醇（E2）处理。血浆 27HC 水平在肥胖男性和女性个体之间与肝炎症标志物呈相反的相关性。同样，肝 27HC 水平在雌性和雄性 Npc1 小鼠之间呈相反的相关性。27HC 注射可降低雌性 Npc1 小鼠的肝炎症，而雄性 Npc1 小鼠在接受 27HC 注射后肝炎症增加。此外，27HC 给药也会对在富含 E2 的培养基中培养的雌性和雄性 BMDM 的炎症产生相反的影响。值得注意的是，雌性 BMDM 中的 ERα 表达高于雄性 BMDM。我们的研究结果表明，27HC 的性别相反的炎症作用是雌激素依赖性的，并且可能与雌性和雄性之间 ERα 表达的差异有关。因此，在将 27HC 用作治疗工具以及在一般的巨噬细胞雌激素研究中，都需要考虑个体的性别。
