Related Experiment Video
Updated: Jan 2, 2026
In vitro Monitoring of Extracellular pH in Real-Time
Published on: June 3, 2021
Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3
Ian M Cartwright1,2,3, Valerie F Curtis1,2, Jordi M Lanis1,2
1Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
Abstract:
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-/HCO3- 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.
Insights
Neutrophil migration into the gut causes inflammation and acidification. Adenosine signaling during this process induces SLC26A3 in intestinal cells, helping to restore pH balance during inflammation.
Area of Science:
- Gastroenterology
- Immunology
- Cell Biology
Background:
- Acute intestinal inflammation involves neutrophil (PMN) accumulation.
- PMN infiltration alters the local tissue microenvironment via oxygen depletion and adenine nucleotide release.
- This study investigates the hypothesis that PMN interaction with intestinal epithelial cells (IECs) causes inflammatory tissue acidification.
Purpose of the Study:
- To determine if active PMN transepithelial migration (TEM) acidifies the intestinal microenvironment.
- To identify acid-adaptive pathways in IECs triggered by PMN TEM.
- To elucidate the role of adenosine (Ado) and SLC26A3 in regulating pH homeostasis during intestinal inflammation.
Main Methods:
- Measurement of microenvironmental pH changes during active PMN TEM.
- Microarray analysis of IEC gene expression in response to Ado.
- Loss- and gain-of-function studies in murine and human colonoids.
- Assessment of SLC26A3 expression in chronic murine colitis models.
Main Results:
- Active PMN TEM significantly acidifies the local microenvironment (nearly 2 pH units decrease).
- Adenosine (Ado) signaling induces the expression of the Cl-/HCO3- exchanger SLC26A3 in IECs.
- Ado-induced SLC26A3 promotes an adaptive IEC phenotype that buffers pH during inflammation.
- SLC26A3 expression is upregulated in chronic DSS-induced colitis models.
Conclusions:
- Adenosine signaling during PMN TEM triggers an adaptive response to inflammatory acidification.
- Induced SLC26A3 expression in IECs plays a crucial role in buffering local pH.
- This mechanism promotes pH homeostasis in the inflamed intestine.
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