Microsomal prostaglandin E synthase-1 gene deletion impairs neuro-immune circuitry of the cholinergic anti-inflammatory pathway in endotoxaemic mouse spleen

Abstract

The cholinergic anti-inflammatory pathway (CAP) is an innate neural reflex where parasympathetic and sympathetic nerves work jointly to control inflammation. Activation of CAP by vagus nerve stimulation (VNS) has paved way for novel therapeutic strategies in treating inflammatory diseases. Recently, we discovered that VNS mediated splenic acetylcholine (ACh) release and subsequent immunosuppression in response to LPS associated inflammation is impaired in mice lacking microsomal prostaglandin E synthase-1 (mPGES-1) expression, a key enzyme responsible for prostaglandin E2 synthesis. Here, we have further investigated the consequences of mPGES-1 deficiency on various molecular/cellular events in the spleen which is critical for the optimal functioning of VNS in endotoxaemic mice. First, VNS induced splenic norepinephrine (NE) release in both mPGES-1 (+/+) and (-/-) mice. Compared to mPGES-1 (+/+), immunomodulatory effects of NE on cytokines were strongly compromised in mPGES-1 (-/-) splenocytes. Interestingly, while LPS increased choline acetyltransferase (ChAT) protein level in mPGES-1 (+/+) splenocytes, it failed to exert similar effects in mPGES-1 (-/-) splenocytes despite unaltered β2 AR protein expression. In addition, nicotine inhibited TNFα release by LPS activated mPGES-1 (+/+) splenocytes in vitro. However, such immunosuppressive effects of nicotine were reversed both in mPGES-1 (-/-) mouse splenocytes and human PBMC treated with mPGES-1 inhibitor. In summary, our data implicate PGE2 as an important mediator of ACh synthesis and noradrenergic/cholinergic molecular events in the spleen that constitute a crucial part of the CAP immune regulation. Our results suggest a possible link between cholinergic and PG system of CAP that may be of clinical significance in VNS treatment.

Interleukin-1 receptor-induced PGE2 production controls acetylcholine-mediated cardiac dysfunction and mortality during scorpion envenomation

“…Also, it is known that the stimulation of the vagus nerve promotes the synthesis of ACh through a mechanism involving T cells, which act as a non-neural source of this neurotransmitter 31 . Similar to our results, a previous study has demonstrated the relationship between the release of this ACh and mPGES-1-dependent PGE 2 production in neuroimmune vagal activity 32 . However, findings in the literature are controversial.…”

Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects

“…Thus, the cholinergic anti-inflammatory pathway between the vagus nerve and the splenic nerve can allow the rapid and precise control of systemic cytokine production and the trafficking of inflammatory cells to distant sites (15,120). In more detail, microsomal prostaglandin E synthase-1 gene and PGE2 in the spleen have a crucial role in bridging the immune and nervous systems influenced by nicotine in vitro (121).…”

Mesenchymal stromal cells alleviate acute respiratory distress syndrome through the cholinergic anti-inflammatory pathway

“…Several studies have shown that PGE2 was a vital regulator for the function of vagus nerve system, 41 and mPGES-1 knockout mice showed the deficiency of ACh release. 42 Here, we show that PGE2 secretion from MSCs play the important role for ACh release, and when PGES-2/PTGES are inhibited, MSCs exhibit decreased abilities to promote ACh production and inhibit inflammatory cytokine expression, highlighting its role in CAP activation. Moreover, Suenaga A reported that intracellular cAMP levels were increased via the PGE2 receptors EP2 and EP4 and could increase the mRNA expression and activity of ChAT.…”