Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation

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dc.citation.articleNumbere2023871118en_US
dc.citation.issueNumber20en_US
dc.citation.journalTitleProceedings of the National Academy of Sciencesen_US
dc.citation.volumeNumber118en_US
dc.contributor.authorCartwright, Ian M.en_US
dc.contributor.authorDowdell, Alexander S.en_US
dc.contributor.authorLanis, Jordi M.en_US
dc.contributor.authorBrink, Kathryn R.en_US
dc.contributor.authorMu, Andrewen_US
dc.contributor.authorKostelecky, Rachael E.en_US
dc.contributor.authorSchaefer, Rachel E.M.en_US
dc.contributor.authorWelch, Nicholeen_US
dc.contributor.authorOnyiah, Joseph C.en_US
dc.contributor.authorHall, Caroline H.T.en_US
dc.contributor.authorGerich, Mark E.en_US
dc.contributor.authorTabor, Jeffrey J.en_US
dc.contributor.authorColgan, Sean P.en_US
dc.contributor.orgSystems, Synthetic, and Physical Biology Programen_US
dc.date.accessioned2021-06-09T20:00:51Zen_US
dc.date.available2021-06-09T20:00:51Zen_US
dc.date.issued2021en_US
dc.description.abstractMetabolic changes associated with tissue inflammation result in significant extracellular acidosis (EA). Within mucosal tissues, intestinal epithelial cells (IEC) have evolved adaptive strategies to cope with EA through the up-regulation of SLC26A3 to promote pH homeostasis. We hypothesized that EA significantly alters IEC gene expression as an adaptive mechanism to counteract inflammation. Using an unbiased RNA sequencing approach, we defined the impact of EA on IEC gene expression to define molecular mechanisms by which IEC respond to EA. This approach identified a unique gene signature enriched in cyclic AMP response element-binding protein (CREB)-regulated gene targets. Utilizing loss- and gain-of-function approaches in cultured epithelia and murine colonoids, we demonstrate that EA elicits prominent CREB phosphorylation through cyclic AMP-independent mechanisms that requires elements of the mitogen-activated protein kinase signaling pathway. Further analysis revealed that EA signals through the G protein-coupled receptor GPR31 to promote induction of FosB, NR4A1, and DUSP1. These studies were extended to an in vivo murine model in conjunction with colonization of a pH reporter Escherichia coli strain that demonstrated significant mucosal acidification in the TNFΔARE model of murine ileitis. Herein, we observed a strong correlation between the expression of acidosis-associated genes with bacterial reporter sfGFP intensity in the distal ileum. Finally, the expression of this unique EA-associated gene signature was increased during active inflammation in patients with Crohn’s disease but not in the patient control samples. These findings establish a mechanism for EA-induced signals during inflammation-associated acidosis in both murine and human ileitis.en_US
dc.identifier.citationCartwright, Ian M., Dowdell, Alexander S., Lanis, Jordi M., et al.. "Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation." <i>Proceedings of the National Academy of Sciences,</i> 118, no. 20 (2021) National Academy of Sciences: https://doi.org/10.1073/pnas.2023871118.en_US
dc.identifier.doihttps://doi.org/10.1073/pnas.2023871118en_US
dc.identifier.urihttps://hdl.handle.net/1911/110701en_US
dc.language.isoengen_US
dc.publisherNational Academy of Sciencesen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the authors.en_US
dc.titleMucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylationen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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