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.
Highlights
The discovery of cholinergic anti-inflammatory pathway (CAP), made a few decades ago, has challenged our understanding of the autonomy of our immune system in many ways including the ability of cytokines to activate nerves and the capacity of immune cells to secrete neurotransmitters
CAP is a combination of both parasympathetic and sympathetic nervous systems that works hand in hand to recognize homeostatic imbalances induced by inflammatory cytokines and respond in a controlled, timely and localized manner to limit inflammation and restore homeostasis
It was suggested that the sympathetic splenic nerve was activated by vagal signaling via post synaptic α7 nicotinic acetylcholine receptors (α7nAChR) in the celiac-mesenteric ganglion [6], this connection is up for debate, and expression of α7nACh receptors on immune cells are shown to be integral for normal functioning of the CAP [7]
Summary
The discovery of cholinergic anti-inflammatory pathway (CAP), made a few decades ago, has challenged our understanding of the autonomy of our immune system in many ways including the ability of cytokines to activate nerves and the capacity of immune cells to secrete neurotransmitters. Onset of peripheral inflammation, caused by the invasion of foreign agents or pathogens, is known to be orchestrated by the amplified production of pro-inflammatory cytokines such as TNFα, IL-1β and IL-8 by activated innate immune cells. Such immune responses eventually result in the elimination of the causative agent and what follows is an active resolution phase and restoration of homeostasis. Functional ChAT expression results in ACh release from T lymphocytes which binds to its receptor α7 nicotinic ACh receptors (α7nAChR) on activated macrophages which downregulates nuclear factor kappa B (NF-κB) dependent pro-inflammatory cytokine production [11]. Spleen is believed to be a central organ for CAP functioning, especially in sepsis and similar inflammatory diseases
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