Overexpression of ATP-activated P2X7 Receptors in the Intestinal Mucosa Is Implicated in the Pathogenesis of Crohnʼs Disease
Abstract
BACKGROUND: Extracellular nucleotides released in conditions of cell stress alert the immune system from tissue injury or inflammation. We hypothesized that the P2X7 receptor (P2X7-R) could regulate key elements in inflammatory bowel disease pathogenesis. METHODS: Colonoscopy samples obtained from patients with Crohn's disease (CD), ulcerative colitis, and controls were used to analyze P2X7-R expression by RT and real-time PCR, immunohistochemistry, and confocal microscopy. Inflammatory response was determined by the levels of cytokines by enzyme-linked immunosorbent assay in cultures of intestinal explants. Apoptosis was determined by the TUNEL assay. P2X7-R C57BL/6 mice were treated with trinitrobenzene sulfonic acid or dextran sulfate sodium (DSS) for inducing colitis. RESULTS: P2X7-R was expressed in higher levels in inflamed CD epithelium and lamina propria, where it colocalizes more with dendritic cells and macrophages. Basal levels of P2X7-R mRNA were higher in CD inflamed mucosa compared with noninflamed CD and controls and were upregulated after interferon-γ in controls. Apoptotic rates were higher in CD epithelium and lamina propria compared with ulcerative colitis and controls. Levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-17 were higher, whereas IL-10 was lower in CD compared with controls. Levels of tumor necrosis factor-α-α and interleukin-1β increased after adenosine-triphosphate and decreased after KN62 treatment in CD. P2X7-R animals did not develop trinitrobenzene sulfonic acid or DSS colitis. CONCLUSIONS: The upregulation of P2X7-R in CD inflamed mucosa is consistent with the involvement of purinoceptors in inflammation and apoptosis. These observations may implicate purinergic signaling in the pathogenesis of intestinal inflammation, and the P2X7-R may represent a novel therapeutic target in CD.
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In humans, polymorphisms of ENTPD1 are associated with IBD, and P2X7 expression is increased in the intestinal epithelium and lamina propria of IBD patients.
“In humans, polymorphisms of ENTPD1 were shown to be associated with IBD, and expression of P2X7 was increased in the intestinal epithelium and lamina propria of IBD patients (Friedman et al., 2009; Neves et al., 2014).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Neves et al., 2014
P2rx7−/− mice were protected against experimental induction of colitis, as were rats treated prophylactically with a chemical P2X7 antagonist.
“P2rx7−/− mice were protected against experimental induction of colitis, as were rats treated prophylactically with a chemical P2X7 antagonist (Marques et al., 2014; Neves et al., 2014).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Neves et al., 2014
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Immunopathogenesis of IBD: current state of the art
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“In humans, polymorphisms of ENTPD1 were shown to be associated with IBD, and expression of P2X7 was increased in the intestinal epithelium and lamina propria of IBD patients (Friedman et al., 2009; Neves et al., 2014).”
BackgroundThe P2X7 Receptor in Inflammatory Diseases: Angel or Demon?
Savio, L. E. B., de Andrade Mello, P., da Silva, C. G., & Coutinho-Silva, R. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00052 · Cited by 437 · see citing works
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- Authors
- Neves, A. R., Castelo-Branco, M. T. L., Figliuolo, V. R., Bernardazzi, C., Buongusto, F., Yoshimoto, A., Nanini, H. F., Coutinho, C. M. L. M., Carneiro, A. J. V., Coutinho-Silva, R., & de Souza, H. S. P.
- Affiliations
- Universidade Federal do Rio de Janeiro (BR)
- Venue
- Inflammatory Bowel Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-03
- Volume
- 20
- Issue
- 3
- Pages
- 444-457
- ISSN
- 1078-0998 (ISSN-L)
- OpenAlex
- W1969485182
- Cited by
- 107
- References
- 76
- Citations by year
- 2026: 10 · 2025: 4 · 2024: 10 · 2023: 8 · 2022: 11 · 2021: 9 · 2020: 4 · 2019: 9 · 2018: 9 · 2017: 13 · 2016: 13 · 2015: 5 · 2014: 2
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Inflammatory Bowel Diseases (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- P2X7 receptor, Crohn's disease
- MeSH terms
- Adenosine Triphosphate, Adolescent, Adult, Animals, Colitis, Ulcerative, Colonoscopy, Crohn Disease, Enzyme-Linked Immunosorbent Assay, Female, Fluorescent Antibody Technique, Follow-Up Studies, Humans, Interferon-gamma, Intestinal Mucosa, Male, Mice, Inbred C57BL, Middle Aged, Prognosis, RNA, Messenger, Tumor Necrosis Factor-alpha, Blotting, Western, Case-Control Studies, Interleukin-10, Apoptosis, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Mice, Interleukin-1beta, Young Adult, Receptors, Purinergic P2X7, Real-Time Polymerase Chain Reaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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