2 | RESEARCH OVERVIEW ON CAP
MECHANISM
Among the key parts of CAP, the effects of vagus nerve and α7nAChR are
relatively identified. In CAP, muscarinic receptors (mAChR), microRNAs
(miRNAs), β2 adrenergic receptors, spleen also play a role in it (Figure
2).
2.1 | Vagus nerve
Anti-inflammatory effect of CAP depends on the integrity of the vagus
nerve. Vagus nerve is the connector of brain and immune system (spleen,
liver, etc.). Inflammatory cytokines released by macrophages, dendritic
cells, and immune cells could locally activate vagus nerve fibers.
Signal is transmitted to nucleus tractus solitarius (NTS) in the medulla
oblongata (Tracey, 2009). NTS takes the integrated information to make a
decision and project it into efferent vagus nerve in the dorsal motor
nucleus, prompting ACh to release at the target organ and activating
cholinergic receptors in macrophages, such as α7nAChR, thereby
inhibiting the generation of inflammatory cytokines (Ulloa, 2005). Vagus
nerve regulation on TNF is one of the most deeply studied
anti-inflammatory mechanisms, and it also reduces the levels of IL-1β,
IL-6, and high mobility group box 1 (HMGB1). Parasympathetic nerves are
involved in controlling the inflammatory responses, while skin and
skeletal muscles can also exhibit cholinergic anti-inflammatory
regulation without vagal innervation. Studies have indicated that vagus
nerve is not a proprietary attribute of inflammatory cholinergic
regulation (Pereira & Leite, 2016). Thus, the regulation of other parts
of CAP needs further study.
2.2 | Nicotinic receptor
Cholinergic receptors are nicotinic receptors (nAChR) and mAChR, the
anti-inflammatory effects of cholinergic transmitters are mainly
mediated by nAChR. nAChR is a member of four transmembrane domains
superfamilies of neurotransmitter-gated ion channels. These receptors
play a central role in regulating synaptic nerve transmission and basic
intracellular signaling, and controlling the viability of neuronal and
the structure of synaptic. Moreover, α7nAChR is the closest receptor to
inflammation and has a high affinity for α-silver snake toxin. It is a
homopentamer that composed of five α7 subunits and is extensively
distributed among macrophages, endothelial cells, lymphocytes, glial
cells, and intestinal epithelial cells, etc. Besides, α7nAChR is
associated with obesity, diabetes, AD, arthritis, asthma,
atherosclerosis, cancer, and psoriasis (Bencherif, Lippiello, Lucas, &
Marrero, 2011). Activation of α7nAChR contained in lymphocytes and
macrophages can regulate their activation, and macrophages mediate the
physiological control of cytokine production by autocrine/paracrine ACh
through nAChR (De Rosa, Dionisio, Agriello, Bouzat, & Esandi Mdel,
2009; Gotti & Clementi, 2004). Activation of α7nAChR can suppress the
release of inflammatory cytokines such as TNF, IL-1β, IL-6, IL-8 and
HMGB1. ACh is the most direct agonist affecting α7nAChR, and related
enzymes such as AChE may have potential therapeutic significance. The
inhibition of AChE is a key way to treat diseases such as AD(Y. Jiang,
Gao, & Turdu, 2017). Therefore, α7nAChR and ACh-related enzymes have
become important targets for inflammation-related diseases treatment.
2.3 | Muscarinic
receptors
The muscarinic receptor (mAChR) is a seven-transmembrane domain G
protein-coupled receptor composed of five different subtypes, namely
M1-M5. It can mediate many biological effects, including the regulation
of heart rate, glandular secretion, smooth muscle contraction, and
central nervous system (Kruse et al., 2014). The role of peripheral
mAChR in inflammation is still controversial. Intravenous injection of
mAChR inhibitor atropine methyl nitrate in endotoxemia rats cannot
eliminate the inhibitory effect of vagal nerve stimulation on TNF, nor
can it inhibit serum TNF(Pavlov et al., 2006). Another study found that
M1 and M5 mAChRs are involved in regulating the production of cytokines
(such as IL-6), resulting in the switch regulation of antibody class
from IgM to IgG1, up-regulating immune response of protein antigens, but
not participating in the initial production response of antibodies
(Fujii et al., 2007). However, further validation of central mAChR
agonists found that the stimulation of nAChR and mAChR significantly
reduced the levels of pro-inflammatory cytokines like IL-1β, IL-6,
macrophage inflammatory protein 2 (MIP-2), and animal mortality in early
sepsis. CAP are regulated mainly by stimulating central mAChR and
peripheral 7nAChR (Zabrodskii, Lim, Shekhter, & Kuzmin, 2012).
Especially in central inflammatory diseases, it may be closely related
to central mAChR, and the mechanism research between them needs to
deepen on mAChR and central inflammation.
2.4 | β2 adrenergic
receptor
Adrenergic receptors (AR) are a large family of seven transmembrane
receptors which respond to catecholamines. Both primary and secondary
immune organs are dominated by plenty of sympathetic nerve fibers
emitted from the sympathetic postganglionic fibers. When the sympathetic
nervous system is excited, the end of the sympathetic nerves that govern
each immune system mainly release norepinephrine (NE), which in turn
causes a local immune response. Vagus nerve stimulation relies on NE
released from splenic sympathetic nerve endings, followed by β2AR
activation in T lymphocytes (Vida et al., 2011). High concentrations of
NE activate lymphocytes, thereby producing ACh in vitro (Rosas-Ballina
et al., 2011). These findings indicate that β2AR activation imitates
CAP. At the same time, β2AR activation can also prevent the development
of sepsis through additional mechanisms in the innate immune system,
such as directly inhibiting cytokine production or increasing bacterial
phagocytosis in macrophages (Muthu et al., 2010; Severn, Rapson, Hunter,
& Liew, 1992).
2.5 | miRNAs
miRNAs regulate gene expression in various biological processes. About
5000-10000 miRNAs are expressed in mammalian cells, which regulate more
than 60% of protein-coding genes. miRNAs rapidly stop mRNA translation
and adjust specific genes expression, prevent the ability of mRNA
translation and degradation more quickly and stronger. It enable CAP to
moderate the acute production of inflammatory cytokines, and limit the
potentially excessively enthusiastic secondary response while
maintaining controlled inflammation monitoring (Ulloa, 2013). miRNAs do
not represent an effective mechanism for completely shutting down gene
expression. Instead, they usually function as a “regulatory” mechanism
that regulates gene expression within range of 1-4 times. This is a
typical feature of the cholinergic anti-inflammatory pathway. It uses
chemical instability and short life cycle of ACh and miRNAs to quickly
regulate inflammation and avoid tissue damage, but maintains baseline
expression of infection. Compared with the immunosuppressive effects of
glucocorticoids, these mechanisms have biological advantages. Clinical
studies have revealed that the function of macrophages in children with
intestinal failure is excessively activated. miRNA-124 directly targets
the 3’ untranslated region of STAT3 and AChE mRNA, inhibits macrophage
activation, reduces IL-6 and TNF-α release, and alleviates abdominal
inflammation (Y. T. Xiao, Wang, Lu, Cao, & Cai, 2016). Nicotinic acid
can induce miRNA-124 through α7nAChR to inhibit STAT3 tyrosine
phosphorylation and protein expression, and negatively regulate the
inflammation caused by Toll-like receptor 4 (TLR4) (Qin, Wang, Su, &
Liu, 2016; Y. Sun et al., 2013). miRNA-124a, miRNA-132 and miRNA-205-5b
are also the key mediator of cholinergic anti-inflammatory activity (Q.
Li, 2011; F. Liu et al., 2015; W. Zhou, Wang, Li, Li, & Sang, 2016). At
present, there are not many drugs studied from this angle, and it is
necessary to further clarify which miRNAs is more closely related to
CAP.
2.6 | Spleen
Anatomically, spleen is necessary for vagus nerve to control
inflammatory response (Huston et al., 2008). Spleen is also the main
source of serum TNF in endotoxemia, and TNF enters systemic circulation
from splenic vein through liver. Vagus nerve regulates cytokines
production through two-stage tandem neurons. Preganglionic neurons are
located in the dorsal nucleus of vagus motor. Postganglionic neurons
come from the superior mesenteric plexus of the abdominal cavity
(Agostoni, Chinnock, De Daly, & Murray, 1957). Splenic nerve fibers are
composed of catecholamine fibers (Klein, Wilson, Dzielak, Yang, &
Viveros, 1982). Similarly, spleen produces ACh, but no ACh nerve fibers
have been detected (Nance & Sanders, 2007), and it is still not
completely clear whether spleen is innervated by vagus nerve. Studies
have found that reserpine consumes catecholamines to eliminate vagal
nerve’s inhibition of TNF (Nezhinskaia, Vladykin, & Sapronov, 2010).
After spleen resection, vagal nerve stimulation specifically reduces TNF
production from macrophages in the red pulp and marginal area
(Rosas-Ballina et al., 2008). And the effect of nicotine on reducing the
level of HMGB1 in the blood of sepsis animals is inhibited (X. M. Song
et al., 2008).