Enhanced lupus progression in alcohol-administered Fc gamma receptor-IIb–deficiency lupus mice, partly through leaky gut-induced inflammation

IF 3.2 4区 医学 Q3 CELL BIOLOGY
Wiwat Chancharoenthana, Supitcha Kamolratanakul, Phatcharapon Yiengwattananon, Pornpimol Phuengmaung, Kanyarat Udompornpitak, Wilasinee Saisorn, Pratsanee Hiengrach, Peerapat Visitchanakun, Marcus J Schultz, Asada Leelahavanichkul
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引用次数: 1

Abstract

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.

Abstract Image

酒精给予的Fc γ受体- iib缺乏性狼疮小鼠狼疮进展增强,部分通过漏性肠诱导炎症
酒精会导致肠道渗漏,微生物分子从肠道转移到血液循环中。虽然炎症对狼疮中器官介导的损伤的贡献已经被证实,但饮酒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Fcγ受体iib缺陷(Fcγ riib−/−)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性炎症和评估粪便生态失调以及内毒素血症。与酒精给药的野生型小鼠相比,FcγRIIb - / -小鼠表现出更明显的肝损伤(酶、组织学评分、细胞凋亡、丙二醛氧化剂)和血清白细胞介素(IL)-6水平,尽管在漏肠(异硫氰酸酯-右糖酐荧光素测定、内毒素血症和肠道occludin-1免疫荧光)、粪便生态失调(微生物组分析)和内毒素血症方面相似。所有给予酒精的FcγRIIb−/−小鼠均表现出狼疮样特征(血清抗dsdna、蛋白尿、血清肌酐和肾损伤评分),并伴有脾脏凋亡,而对照FcγRIIb−/−小鼠仅表现出轻微的抗dsdna。酒精和脂多糖(LPS)同样会损害肠细胞的完整性(经上皮电阻),并且只有LPS而不是酒精上调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显著诱导这两个参数(在FcγRIIb−/−巨噬细胞中比野生型更明显)。在肠细胞和巨噬细胞中,与单独使用LPS相比,LPS加酒精没有协同作用。总之,酒精可能在一定程度上通过FcγRIIb−/−小鼠漏肠的深度炎症加剧狼疮样活动。
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来源期刊
Immunology & Cell Biology
Immunology & Cell Biology 医学-免疫学
CiteScore
7.50
自引率
2.50%
发文量
98
审稿时长
4-8 weeks
期刊介绍: The Australasian Society for Immunology Incorporated (ASI) was created by the amalgamation in 1991 of the Australian Society for Immunology, formed in 1970, and the New Zealand Society for Immunology, formed in 1975. The aim of the Society is to encourage and support the discipline of immunology in the Australasian region. It is a broadly based Society, embracing clinical and experimental, cellular and molecular immunology in humans and animals. The Society provides a network for the exchange of information and for collaboration within Australia, New Zealand and overseas. ASI members have been prominent in advancing biological and medical research worldwide. We seek to encourage the study of immunology in Australia and New Zealand and are active in introducing young scientists to the discipline.
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