3 | RELATIONSHIP BETWEEN CAP AND MAIN RELATED
PATHWAYS
3.1 | JAK/STAT pathway
JAK/STAT pathway is involved in inflammation and immune responses with
duality. Firstly, JAK/STAT1 is the transcription pathway of HMGB1, that
is, LPS induces macrophages to release HMGB1 through the
TLR4/IFN-β/STAT1 signal axis. Secondly, α7nAChR regulates JAK2/STAT3
after being activated. After vagus nerve stimulation or α7nAChR
activation, JAK2 is recruited to α7nAChR to form a heterodimeric
complex. By phosphorylating STAT3 to reduce the nuclear translocation of
NF-κB (de Jonge et al., 2005), STAT3 acts as a dominant-negative
inhibitor of NF-κB DNA binding activity and directly inhibits
pro-inflammatory cytokines induction by interacting with NF-κB p65 (Yu,
Zhang, & Kone, 2002). STAT3 is not directly connected to
pro-inflammatory cytokines production, and attenuated cytokine
expression mediated by α7nAChR stimulation is a synergy between NF-κB
and JAK/STAT (shown in Figure 2C) (Tasaka et al., 2015). Cholinergic
agonists (nicotine and GTS-21) inhibit IL-6-mediated MCP-1 production
and ICAM-1 expression through JAK2/STAT3 pathway in a SHP1/2
phosphatase-dependent manner. It is associated with a reduction of JAK2
and STAT3 phosphorylation, STAT3-specific DNA binding, and reduction of
suppressor of cytokine signaling 3 (SOCS3, a regulator of the JAK2/STAT3
pathway) levels (Chatterjee, Al-Abed, Sherry, & Metz, 2009). Especially
in the anti-inflammatory and inhibitory cell apoptosis pathways, α7nAChR
plays a key role in JAK2/STAT3 and NF-κB (Marrero & Bencherif, 2009).
Normally, activation of α7nAChR and inhibition of JAK2 can attenuate
STAT3 phosphorylation to exert subsequent responses, while α7nAChR
signaling requires STAT3 protein rather than its tyrosine
phosphorylation. Unphosphorylated STAT3 can also compete with an
inhibitor of NF-κB α (IκBα) to bind NF-κB and inhibit TNF
transcriptional activation to regulate the innate immune response during
infection. However, the STAT3–NF-κB complex may enhance the production
of other cytokines (Peña et al., 2010).
3.2 | NF-κB pathway
NF-κB inhibition can reduce inflammation and inhibit
macrophages/monocytes to play a key role in innate immune response.
While NF-κB is activated by microbial components (such as LPS,
peptidoglycan, dsRNA, etc.) through TLR. The downstream signaling
cascade includes IκB kinase (IKK) activation, IκB phosphorylation, NF-κB
translocation, and subsequent gene transcription. Meanwhile, NF-κB is
also regulated by JAK2/STAT3, as described in 3.1. α7nAChR
activation-mediated CAP prevents NF-κB nuclear translocation in
macrophages, while nicotine inhibits IKK phosphorylation and NF-κB
transcriptional activity through α7nAChR signaling (Yoshikawa et al.,
2006). In sepsis, α7nAChR-mediated anti-inflammatory and TLR4-mediated
pro-inflammatory pathways are activated, and several pro-inflammatory
cytokines are released. The classic anti-inflammatory drug dexamethasone
can also inhibit proinflammatory cytokines by up-regulating α7nAChR and
ACh, and inhibits TLR4/MyD88/NF-κB pathway, thereby inhibiting
inflammation. The specific α7nAChR antagonist α-bungarotoxin eliminates
the effects of dexmedetomidine (Zi et al., 2019).
3.3 | MAPK pathway
Mitogen-activated protein kinase (MAPK) signaling pathway includes c-Jun
N-terminal kinase (JNK), extracellular regulated protein kinases (ERK),
and P38 MAPK. These components can act both independently and
synergistically. MAPK activation requires the phosphorylation of its
specific amino acid sequence, combined with stimulation of other
kinases, translocates to the nucleus and activates the transcription of
proinflammatory genes. MAPK is closely related to the downstream NF-κB
in CAP and plays an important role in inflammation. Regulation of
α7nAChR activation by microglia on inflammatory mediators is achieved by
inhibiting the P38 and ERK pathways in the MAPK pathway (Lei, 2009). In
colitis model, the improvement of vagal activity may activate ERK1/2 and
NF-κB translocation, and induce the transcription of proinflammatory
genes through the interaction of α7nAChR and the peripheral release of
ACh in the inflamed colonic mucosa (P. Sun et al., 2013). K opioid
receptor agonists can activate α7nAChR through MAPK-ERK1/2 signaling
pathway, regulate CAP, inhibit NF-κB expression, reduce inflammation,
and postoperative cognitive dysfunction caused by cardiopulmonary bypass
(Fan, Duan, & Sun, 2019). Ligation-induced acute pancreatitis in rats
is related to the continuous increase of M3 mAChR expression in a
time-dependent manner and is also related to the increase in the
activation of stress-activated protein kinase JNK (Samuel, Zaheer,
Fisher, & Zaheer, 2003). JNK is a major negative regulator of
intestinal secretion induced by mAChR. mAChR stimulation increases the
phosphorylation of MAPKs and is inhibited by MAPK inhibitors (Khan et
al., 2015). Also, activation of α7nAChR (selective agonist PNU282987)
significantly reduces apoptosis and intracellular oxidative stress
levels and prevents oxidative stress-induced damage by inhibiting the
vascular peroxidase-1 in endothelial cells in a JNK signaling
pathway-dependent manner (D. J. Li et al., 2014). Consequently, MAPK
signaling pathway can also play a role in CAP-mediated inflammation, and
its relationship with JAK2/STAT3 and NF-κB in CAP is complex.
3.4 | PI3K/Akt pathway
PI3K pathway responds to the activation of pro-inflammatory signaling
pathway in cells to some extent in the immune defense mechanism
(Williams et al., 2004). Activation of α7nAChR results in formation of
heterodimeric complexes between α7nAChR protein and JAK2, which can
initiate signal transduction mediated by STAT3, followed by PI3K
tyrosine phosphorylation and Akt serine phosphorylation (Shaw,
Bencherif, & Marrero, 2002). The relationship between PI3K and TLR4 is
still not completely clear and may be bidirectional. On the one hand,
TLR4 activates PI3K to limit TNF-α production, and the pharmacological
blockade of PI3K leads to enhanced activation of NF-κB (Chaurasia et
al., 2010). At the same time, it is also possible that PI3K negatively
regulates TLR4. PI3K/Akt activation can reduce apoptosis and TLR4
expression, and PI3K inhibitors can increase local inflammation (Ke et
al., 2012). Studies have revealed that nicotine inhibits the
overexpression of TLR4 by activating the α7nAChR/PI3K pathway, and
PI3K/Akt plays a negative feedback role in it (T. H. Kim, Kim, & Lee,
2014).