Epithelial CaSR deficiency alters intestinal integrity and promotes proinflammatory immune responses

Abstract

The intestinal epithelium is equipped with sensing receptor mechanisms that interact with luminal microorganisms and nutrients to regulate barrier function and gut immune responses, thereby maintaining intestinal homeostasis. Herein, we clarify the role of the extracellular calcium-sensing receptor (CaSR) using intestinal epithelium-specific Casr−/− mice. Epithelial CaSR deficiency diminished intestinal barrier function, altered microbiota composition, and skewed immune responses towards proinflammatory. Consequently, Casr−/− mice were significantly more prone to chemically induced intestinal inflammation resulting in colitis. Accordingly, CaSR represents a potential therapeutic target for autoinflammatory disorders, including inflammatory bowel diseases.

Calcium-sensing receptor stimulates Cl−- and SCFA-dependent but inhibits cAMP-dependent HCO3− secretion in colon

“…To provide insight into the mechanisms by which CaSR may regulate different HCO 3 Ϫ secretory processes, the effects of R568 on the Cl Ϫ /HCO 3 Ϫ and SCFA/ HCO 3 Ϫ exchanges (which are electroneutral and thus can be measured by pH stat) and electrogenic HCO 3 Ϫ movement (thus can be measured by I sc and pH stat) were examined, both in rats and in CaSR wild-type and mutant mice. We have previously demonstrated that CaSR agonists can inhibit fluid/Cl Ϫ secretion (10,12,14,16,25) and mucosa inflammation (11,15). These present studies show that CaSR agonists can also exert their effects on mucosal biology and physiology through differentially regulating HCO 3 Ϫ secretion.…”

“…Thus the ability for CaSR to stimulate HCO 3 Ϫ secretion under basal conditions suggests that, through modulating mucus secretion and barrier function, this well-conserved nutrientsensing receptor may play a role in intestinal immune function. Indeed, mice deficient in CaSR with deficient regulated HCO 3 Ϫ secretion in the colon have altered barrier integrity, enhanced bacteria translocation, and increased inflammation (15,30), whereas enteral nutrients, including the CaSR-activating nutrients/minerals, calcium, spermine, and tryptophan, have been shown to improve intestinal permeability and immunity (39,40) and inflammation (5,6,11,13).…”

“…The role of CaSR in basal and acid-induced HCO 3 Ϫ secretion is unknown although a recent study with gut-specific CaSR knockout mice suggests that this receptor is crucial for mucosal defense and immunity (15).…”

The role of the calcium-sensing receptor in gastrointestinal inflammation

“…Epithelial CaSR deficiency diminished intestinal barrier function, altered the composition of the microbiota, and skewed immunity towards a proinflammatory response [72]. Assessment of intestinal permeability was performed ex vivo using Ussing chambers; Casr −/− mice exhibited reduced transepithelial resistance (TEER), and higher transepithelial conductance ( G T ) and passive transport of FITC-conjugated dextran.…”

The Calcium-Sensing Receptor Gene Polymorphism rs1801725 and Calcium-Related Phenotypes in Hemodialysis Patients

“…Involvement of CaSR or its activators in infectious diseases was suggested in several studies [38, 39]. Human peripheral blood monocytes possess both CaR protein and mRNA [40].…”