Decreased expression of DRA (SLC26A3) by a p38-driven IL-1α response contributes to diarrheal disease following in vivo challenge with Brachyspira spp.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Nitin Challa, Cole B Enns, Brandon A Keith, John C S Harding, Matthew E Loewen
{"title":"Decreased expression of DRA (<i>SLC26A3</i>) by a p38-driven IL-1α response contributes to diarrheal disease following in vivo challenge with <i>Brachyspira</i> spp.","authors":"Nitin Challa, Cole B Enns, Brandon A Keith, John C S Harding, Matthew E Loewen","doi":"10.1152/ajpgi.00049.2023","DOIUrl":null,"url":null,"abstract":"<p><p>In this study, we uncovered the novel mechanism of IL-1α-mediated downregulated in adenoma (DRA) (<i>SLC26A3</i>) downregulation in the context of <i>Brachyspira</i> spp.<i>-</i>induced malabsorptive diarrhea. Experimentally infected pigs with <i>Brachyspira</i> spp. had significantly reduced DRA expression in the colon accompanied by IL-1α upregulation. This response was recapitulated in vitro by exposing Caco-2 cells to either <i>Brachyspira</i> lysate or IL-1α. Both p38 and MAPK-activated protein kinase 2 (MAPKAPK-2 also referred as MK-2) showed an increased phosphorylation after exposure to either. SB203580 application, a p38 inhibitor blocked the MK-2 phosphorylation and attenuated the DRA and IL-1α response to both lysate and IL-1α. Exposure to IL-1 receptor antagonist (IL-1RA) produced a similar response. In addition, exposure of cells to either of these blockers without IL-1α or lysate results in increased DRA and decreased IL-1α expression, revealing that DRA needs IL-1α signaling for basal physiological expression. Dual inhibition with both blockers completely inhibited the effect from IL-1α while significantly attenuating the response from <i>Brachyspira</i> lysate, suggesting a minor contribution from another pathway. Together this demonstrates that <i>Brachyspira</i> activates p38 MAPK signaling driving IL-1α expression, which activates IL-1R1 causing DRA downregulation while also driving upregulation of IL-1α through p38 in a positive feedback mechanism. In conclusion, we elucidated a major pathway involved in DRA downregulation and its role in <i>Brachyspira</i>-induced diarrhea. In addition, these observations will aid in our understanding of other inflammatory and infectious diarrhea conditions.<b>NEW & NOTEWORTHY</b> The diarrheal disease caused by the two infectious spirochete spp. <i>B. hyodysenteriae</i> and <i>B. hampsonii</i> reduced the expression of DRA (<i>SLC26A3</i>), a major Cl<sup>-</sup>/HCO<sup>-</sup><sub>3</sub> exchanger involved in Cl<sup>-</sup> absorption. This is attributed to the upregulation of IL-1α driven by p38 MAPK. This work also describes a potential new mechanism in inflammatory diseases while showing the importance of IL-1α in maintaining DRA levels.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G655-G672"},"PeriodicalIF":3.9000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Gastrointestinal and liver physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajpgi.00049.2023","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/6 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

In this study, we uncovered the novel mechanism of IL-1α-mediated downregulated in adenoma (DRA) (SLC26A3) downregulation in the context of Brachyspira spp.-induced malabsorptive diarrhea. Experimentally infected pigs with Brachyspira spp. had significantly reduced DRA expression in the colon accompanied by IL-1α upregulation. This response was recapitulated in vitro by exposing Caco-2 cells to either Brachyspira lysate or IL-1α. Both p38 and MAPK-activated protein kinase 2 (MAPKAPK-2 also referred as MK-2) showed an increased phosphorylation after exposure to either. SB203580 application, a p38 inhibitor blocked the MK-2 phosphorylation and attenuated the DRA and IL-1α response to both lysate and IL-1α. Exposure to IL-1 receptor antagonist (IL-1RA) produced a similar response. In addition, exposure of cells to either of these blockers without IL-1α or lysate results in increased DRA and decreased IL-1α expression, revealing that DRA needs IL-1α signaling for basal physiological expression. Dual inhibition with both blockers completely inhibited the effect from IL-1α while significantly attenuating the response from Brachyspira lysate, suggesting a minor contribution from another pathway. Together this demonstrates that Brachyspira activates p38 MAPK signaling driving IL-1α expression, which activates IL-1R1 causing DRA downregulation while also driving upregulation of IL-1α through p38 in a positive feedback mechanism. In conclusion, we elucidated a major pathway involved in DRA downregulation and its role in Brachyspira-induced diarrhea. In addition, these observations will aid in our understanding of other inflammatory and infectious diarrhea conditions.NEW & NOTEWORTHY The diarrheal disease caused by the two infectious spirochete spp. B. hyodysenteriae and B. hampsonii reduced the expression of DRA (SLC26A3), a major Cl-/HCO-3 exchanger involved in Cl- absorption. This is attributed to the upregulation of IL-1α driven by p38 MAPK. This work also describes a potential new mechanism in inflammatory diseases while showing the importance of IL-1α in maintaining DRA levels.

p38驱动的IL-1α反应导致DRA (SLC26A3)表达减少,从而导致体内感染 Brachyspira spp后出现腹泻病。
在本研究中,我们发现了在布拉希茨弧菌诱导的吸收不良性腹泻中,IL-1α介导的DRA(SLC26A3)下调的新机制。实验性感染 Brachyspira spp.的猪结肠中 DRA 的表达明显减少,同时 IL-1α 上调。将 Caco-2 细胞暴露于 Brachyspira 裂解液或 IL-1α 中,可在体外重现这种反应。p38 和 MK-2 在接触这两种物质后都显示出磷酸化增加。应用 SB203580(一种 p38 抑制剂)可阻止 MK-2 磷酸化,并减轻 DRA 和 IL-1α 对裂解物和 IL-1α 的反应。接触 IL-1 受体拮抗剂(IL-1RA)也会产生类似的反应。此外,将细胞暴露于不含 IL-1α 或裂解物的这两种阻断剂中的任何一种都会导致 DRA 表达的增加和 IL-1α 表达的减少,这揭示了 DRA 的基础生理表达需要 IL-1α 信号传导。两种阻断剂的双重抑制作用完全抑制了 IL-1α 的作用,同时显著减弱了布拉希梭菌裂解物的反应,这表明另一种途径也有微小的作用。综上所述,这表明布拉奇斯匹拉病毒激活 p38 MAPK 信号,驱动 IL-1α 的表达,从而激活 IL-1R1 导致 DRA 下调。同时还通过 p38 在正反馈机制中驱动 IL-1α 的上调。总之,我们阐明了 DRA 下调的主要途径及其在布拉希茨弧菌诱导的腹泻中的作用。此外,这些观察结果将有助于我们了解其他炎症和感染性腹泻病症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信