Tojapride prevents CaSR‐mediated NLRP3 inflammasome activation in oesophageal epithelium irritated by acidic bile salts
Open Access
- 20 December 2019
- journal article
- research article
- Published by Wiley in Journal of Cellular and Molecular Medicine
- Vol. 24 (2), 1208-1219
- https://doi.org/10.1111/jcmm.14631
Abstract
Impairment of the oesophageal epithelium in patients with reflux oesophagitis (RE) is a cytokine‐mediated injury rather than a chemical burn. The present study was conducted to explore CaSR/NLRP3 inflammasome pathway activation and cytokines IL‐1β and IL‐18 release in oesophageal epithelia injured by refluxates and the effects of Tojapride on that signal regulation. Using a modified RE rat model with Tojapride administration and Tojapride‐pretreated SV40‐immortalized human oesophageal epithelial cells (HET‐1A) exposed to acidic bile salts pretreated with Tojapride, we evaluated the therapeutic effects of Tojapride on oesophageal epithelial barrier function, the expression of CaSR/NLRP3 inflammasome pathway‐related proteins and the release of downstream cytokines in response to acidic bile salt irritation. In vivo, Tojapride treatment ameliorated the general condition and pathological lesions of the oesophageal epithelium in modified RE rats. In addition, Tojapride effectively blocked the CaSR‐mediated NLRP3 inflammasome activation in modified RE rats. In vitro, Tojapride treatment can reverse the harmful effect of acidic bile salts, which reduced transepithelial electrical resistance (TEER), up‐regulated the CaSR‐mediated NLRP3 inflammasome pathway and increased caspase‐1 activity, LDH release and cytokines secretion. Taken together, these data show that Tojapride can prevent CaSR‐mediated NLRP3 inflammasome activation and alleviate oesophageal epithelial injury induced by acidic bile salt exposure.Keywords
Funding Information
- National Natural Science Foundation of China (Z161100000116046, Z141100002214012, 81503560)
- Beijing Municipal Science and Technology Commission
This publication has 40 references indexed in Scilit:
- Acid and Bile Salt–Induced CDX2 Expression Differs in Esophageal Squamous Cells From Patients With and Without Barrett's EsophagusGastroenterology, 2010
- The role of acid and bile reflux in oesophagitis and Barrett's metaplasiaBiochemical Society Transactions, 2010
- Gastroesophageal Reflux Might Cause Esophagitis Through a Cytokine-Mediated Mechanism Rather Than Caustic Acid InjuryGastroenterology, 2009
- Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 ExpressionThe Journal of Immunology, 2009
- The Functions and Roles of the Extracellular Ca2+–Sensing Receptor along the Gastrointestinal TractAnnual Review of Physiology, 2009
- The influence of co‐morbid IBS and psychological distress on outcomes and quality of life following PPI therapy in patients with gastro‐oesophageal reflux diseaseAlimentary Pharmacology & Therapeutics, 2008
- The extracellular calcium-sensing receptor (CaSR) on human esophagus and evidence of expression of the CaSR on the esophageal epithelial cell line (HET-1A)American Journal of Physiology-Gastrointestinal and Liver Physiology, 2008
- Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cellsAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2007
- Cryopyrin activates the inflammasome in response to toxins and ATPNature, 2006
- The extracellular calcium sensing receptor is expressed in mouse mesangial cells and modulates cell proliferationExperimental & Molecular Medicine, 2005