Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Tropical Immunology and Translational Research Unit (TITRU), Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Immunol Cell Biol. 2023 Sep;101(8):746-765. doi: 10.1111/imcb.12675. Epub 2023 Aug 14.
Alcohol can induce a leaky gut, with translocation of microbial molecules from the gut into the blood circulation. Although the contribution of inflammation to organ-mediated damage in lupus has been previously demonstrated, the mechanistic roles of alcohol consumption in lupus activation are not known. Herein, we tested the effects of 10-week lasting alcohol administration on organ damages and immune responses in 8-week-old lupus-prone Fc gamma receptor IIb-deficient (FcγRIIb ) mice. Our study endpoints were evaluation of systemic inflammation and assessment of fecal dysbiosis along with endotoxemia. In comparison with alcohol-administered wild-type mice, FcγRIIb mice demonstrated more prominent liver damage (enzyme, histological score, apoptosis, malondialdehyde oxidant) and serum interleukin(IL)-6 levels, despite a similarity in leaky gut (fluorescein isothiocyanate-dextran assay, endotoxemia and gut occludin-1 immunofluorescence), fecal dysbiosis (microbiome analysis) and endotoxemia. All alcohol-administered FcγRIIb mice developed lupus-like characteristics (serum anti-dsDNA, proteinuria, serum creatinine and kidney injury score) with spleen apoptosis, whereas control FcγRIIb mice showed only a subtle anti-dsDNA. Both alcohol and lipopolysaccharide (LPS) similarly impaired enterocyte integrity (transepithelial electrical resistance), and only LPS, but not alcohol, upregulated the IL-8 gene in Caco-2 cells. In macrophages, alcohol mildly activated supernatant cytokines (tumor necrosis factor-α and IL-6), but not M1 polarization-associated genes (IL-1β and iNOS), whereas LPS prominently induced both parameters (more prominent in FcγRIIb macrophages than wild type). There was no synergy in LPS plus alcohol compared with LPS alone in both enterocytes and macrophages. In conclusion, alcohol might exacerbate lupus-like activity partly through a profound inflammation from the leaky gut in FcγRIIb mice.
酒精可导致肠道渗漏，使微生物分子从肠道转移到血液循环中。虽然先前已经证明了炎症对狼疮中器官介导损伤的贡献，但酒精摄入在狼疮激活中的机制作用尚不清楚。在此，我们测试了持续 10 周的酒精给药对 8 周龄狼疮易感 Fc 受体 IIb 缺陷（FcγRIIb）小鼠器官损伤和免疫反应的影响。我们的研究终点是评估全身炎症和粪便菌群失调以及内毒素血症。与酒精处理的野生型小鼠相比，尽管肠道渗漏（荧光素异硫氰酸酯-葡聚糖测定、内毒素血症和肠道闭合蛋白-1 免疫荧光）、粪便菌群失调（微生物组分析）和内毒素血症相似，但 FcγRIIb 小鼠表现出更明显的肝损伤（酶、组织学评分、细胞凋亡、丙二醛氧化）和血清白细胞介素（IL）-6 水平。所有接受酒精处理的 FcγRIIb 小鼠均出现狼疮样特征（血清抗 dsDNA、蛋白尿、血清肌酐和肾脏损伤评分）伴脾脏细胞凋亡，而对照 FcγRIIb 小鼠仅出现轻微的抗 dsDNA。酒精和脂多糖（LPS）均同样损害肠上皮细胞完整性（跨上皮电阻），仅 LPS 而非酒精上调 Caco-2 细胞中的 IL-8 基因。在巨噬细胞中，酒精轻度激活上清液细胞因子（肿瘤坏死因子-α和 IL-6），但不激活 M1 极化相关基因（IL-1β和 iNOS），而 LPS 则明显诱导这两个参数（在 FcγRIIb 巨噬细胞中比野生型更明显）。在肠上皮细胞和巨噬细胞中，LPS 加酒精与单独 LPS 相比没有协同作用。总之，酒精可能通过 FcγRIIb 小鼠肠道渗漏引起的严重炎症加剧狼疮样活性。
