{"title":"Enhanced lupus progression in alcohol-administered Fc gamma receptor-IIb–deficiency lupus mice, partly through leaky gut-induced inflammation","authors":"Wiwat Chancharoenthana, Supitcha Kamolratanakul, Phatcharapon Yiengwattananon, Pornpimol Phuengmaung, Kanyarat Udompornpitak, Wilasinee Saisorn, Pratsanee Hiengrach, Peerapat Visitchanakun, Marcus J Schultz, Asada Leelahavanichkul","doi":"10.1111/imcb.12675","DOIUrl":null,"url":null,"abstract":"<p>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<sup>−/−</sup>) 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<sup>−/−</sup> 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<sup>−/−</sup> mice developed lupus-like characteristics (serum anti-dsDNA, proteinuria, serum creatinine and kidney injury score) with spleen apoptosis, whereas control FcγRIIb<sup>−/−</sup> 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 (<i>IL-1β</i> and <i>iNOS</i>), whereas LPS prominently induced both parameters (more prominent in FcγRIIb<sup>−/−</sup> 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<sup>−/−</sup> mice.</p>","PeriodicalId":179,"journal":{"name":"Immunology & Cell Biology","volume":"101 8","pages":"746-765"},"PeriodicalIF":3.2000,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imcb.12675","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunology & Cell Biology","FirstCategoryId":"2","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/imcb.12675","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
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.
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.