Calcium-sensing receptor protects intestinal integrity and alleviates the inflammatory response via the Rac1/PLCγ1 signaling pathway

This study aimed to test the hypothesis that the calcium-sensing receptor (CaSR) can protect intestinal epithelial barrier integrity and decrease inflammatory response mediated by the Ras-related C3 botulinum toxin substrate 1 (Rac1)/phospholipase C gamma 1 (PLC-gamma 1) signaling pathway. IPEC-J2 monolayers were treated without or with TNF-alpha in the absence or presence of CaSR antagonist (NPS 2143), CaSR overexpression, and Rac1 silencing, PLC gamma 1 silencing or spermine. Results showed that spermine increased transepithelial electrical resistance (TER), tight junction protein levels, the protein concentration of Rac1/PLC-gamma 1 signaling pathway, and decreased paracellular permeability in the presence of TNF-alpha. NPS2143 inhibited spermine-induced change in above-mentioned parameters. CaSR overexpression increased TER, the levels of tight junction proteins and the protein concentration of CaSR, phosphorylated PLC gamma 1, Rac1, and IP3, and decreased paracellular permeability and contents of interleukin-8 (IL-8) and TNF-alpha after TNF-alpha challenge. Rac1 and PLC gamma 1 silencing inhibited CaSR-induced increase in barrier function and the protein concentration of phosphorylated PLC gamma 1, Rac1, and IP3, and decrease in contents of IL-8 and TNF-alpha after TNF-alpha challenge. These results suggest that CaSR activation protects intestinal integrity and alleviates the inflammatory response by activating Rac1 and PLC gamma 1 signaling after TNF-alpha challenge, and spermine can maintain barrier function via CaSR/Rac1/PLC-gamma 1 pathway.

Automated summary

This study suggests that activation of CaSR can protect intestinal integrity and alleviate inflammatory response by regulating Rac1 and PLC-γ1 signaling pathways after TNF-α challenge. Additionally, spermine can maintain barrier function via the CaSR/Rac1/PLC-γ1 pathway.