Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3.

Autor: Cartwright IM; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, 80045, USA., Curtis VF; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Lanis JM; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Alexeev EE; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Welch N; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Goldberg MS; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Schaefer REM; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Gao RY; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Chun C; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Fennimore B; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Onyiah JC; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, 80045, USA., Gerich ME; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA., Dempsey PJ; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.; Department of Pediatrics, Children's Hospital of Colorado, Aurora, CO, 80045, USA., Colgan SP; Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Sean.Colgan@UCDenver.edu.; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Sean.Colgan@UCDenver.edu.; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, 80045, USA. Sean.Colgan@UCDenver.edu.
Jazyk: angličtina
Zdroj: Mucosal immunology [Mucosal Immunol] 2020 Mar; Vol. 13 (2), pp. 230-244. Date of Electronic Publication: 2019 Dec 02.
DOI: 10.1038/s41385-019-0237-2
Abstrakt: Acute intestinal inflammation includes the early accumulation of neutrophils (PMN). Based on recent evidence that PMN infiltration "imprints" changes in the local tissue environment through local oxygen depletion and the release of adenine nucleotides, we hypothesized that the interaction between transmigrating PMN and intestinal epithelial cells (IECs) results in inflammatory acidification of the tissue. Using newly developed tools, we revealed that active PMN transepithelial migration (TEM) significantly acidifies the local microenvironment, a decrease of nearly 2 pH units. Using unbiased approaches, we sought to define acid-adaptive pathways elicited by PMN TEM. Given the significant amount of adenosine (Ado) generated during PMN TEM, we profiled the influence of Ado on IECs gene expression by microarray and identified the induction of SLC26A3, the major apical Cl - /HCO 3 - exchanger in IECs. Utilizing loss- and gain-of-function approaches, as well as murine and human colonoids, we demonstrate that Ado-induced SLC26A3 promotes an adaptive IECs phenotype that buffers local pH during active inflammation. Extending these studies, chronic murine colitis models were used to demonstrate that SLC26A3 expression rebounds during chronic DSS-induced inflammation. In conclusion, Ado signaling during PMN TEM induces an adaptive tissue response to inflammatory acidification through the induction of SLC26A3 expression, thereby promoting pH homeostasis.
Databáze: MEDLINE
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