Impaired vagus-mediated immunosuppression in microsomal prostaglandin E synthase-1 deficient mice

Abstract

The cholinergic anti-inflammatory pathway controls innate immune responses and inflammation. The prostaglandin (PG) system is involved in several neuro-processes and associated with inflammatory activation of cells in vagal nuclei. Here we aimed to investigate the potential role of PG in cholinergic neuro-regulation. The effect of vagus nerve stimulation (VNS) has been evaluated in microsomal prostaglandin E synthase-1 (mPGES-1) knockout (-/-) and wild-type (+/+) mice regarding cytokine and PG levels after lipopolysaccharides (LPS) challenge. As expected, VNS decreased the release of pro-inflammatory cytokines both in serum and spleen extracts of mPGES-1 (+/+)animals. However, the immune suppressive effect of VNS was completely abolished in mPGES-1 (-/-) mice. The PG content was not affected by VNS in the spleen of mPGES-1 (+/+) and mPGES-1 (-/-) mice but interestingly, acetylcholine (ACh) release in spleen induced by VNS confirmed an intact cholinergic pathway in mPGES-1 (+/+) whereas no VNS-induced ACh release was found in mPGES-1 (-/-) animals. Our data show that mPGES-1 and consequently PGE2 are crucial in the cholinergic anti-inflammatory pathway. Moreover, the mechanisms involved do not affect PG content in the spleen, but lack of mPGES-1 was found to strongly affect cholinergic mechanisms in the inflamed spleen. These findings illustrate previously unrecognized associations between the cholinergic and prostaglandin systems, and may be of importance for further development of therapeutic strategies directed at modulation of the inflammatory reflex, and immunosuppression in chronic inflammatory diseases.

Keywords: Cholinergic anti-inflammatory pathway; PGE(2); Prostaglandins; Vagus nerve stimulation; mPGES-1 knockout mice.