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

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 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Microbial‐derived indoles inhibit neutrophil myeloperoxidase to diminish bystander tissue damage

“…All protocols were approved by the University's Institutional Animal Care and Use Committee (IACUC). Induction of colitis in mice with the colitogen DSS was performed as previously described 29,38,42,45‐47 . Briefly, DSS (MW = 36 000 – 50 000, MP Biomedicals# 0216011080) was administered at 2.5% (w/v) in drinking water to mice (9‐12 weeks old) for 9 days.…”

“…T84 colorectal adenocarcinoma cells (ATCC# CCL-248) are a well-characterized in vitro model of the colonic intestinal epithelium and were grown as previously described. [38][39][40][41][42][43][44][45] Briefly, cells were cultured at 37°C, 5% CO 2 in 1:1 DMEM/ F-12 (Thermo Fisher# 11330-032) supplemented with heatinactivated bovine calf serum (HyClone# SH30072.03), GlutaMAX (Thermo Fisher# 35050-061), and penicillin/ streptomycin (Thermo Fisher# 15140-122). Cells were passaged weekly using trypsin (Thermo Fisher# 25200-056) dissociation and sub-cultured into 6-well plates.…”

“…Induction of colitis in mice with the colitogen DSS was performed as previously described. 29,38,42,[45][46][47] Briefly, DSS (MW = 36 000 -50 000, MP Biomedicals# 0216011080) was administered at 2.5% (w/v) in drinking water to mice (9-12 weeks old) for 9 days. IPA was given at 0.1 mg/mL in drinking water through the course of the experiment to one age-and sex-matched cohort.…”

Metabolic Host–Microbiota Interactions in Autophagy and the Pathogenesis of Inflammatory Bowel Disease (IBD)

“…Recently, a strain of S. cerevisiae has been engineered to sense extracellular ATP (eATP) in the gut and respond by secretion of recombinant apyrase, catalyzing the degradation of eATP to eAMP [ 171 ]. The resulting eAMP is further degraded to extracellular adenosine by CD73, which is ubiquitously expressed on the apical face of the intestinal epithelium; the resulting extracellular adenosine (eAdo) has been shown to be protective during intestinal inflammation through diverse mechanisms [ 172 , 173 , 174 ]. Scott et al demonstrate that eAdo-generating S. cerevisiae attenuates intestinal inflammation during chemically induced colitis models (DSS and TNBS) and show that engineered S. cerevisiae administration limits inflammation induced fibrosis and dysbiosis [ 171 ].…”

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