FIGURE 2 Regulation of cholinergic anti-inflammatory pathway
(A) The brain contains the nicotinic acetylcholine receptor α7 (α7nAChR)
and muscarinic acetylcholine receptor (mAChR). Inflammatory cytokines
are produced when the body stimulated by LPS and introduced into the
nucleus tractus solitarius (NTS) of the brain via the vagus nerve. Brain
integrates information and makes decisions, the vagus nerve activated
reflexively and sends a signal to the spleen through splenic nerve.
(B) In spleen, norepinephrine (NE) releases and stimulates β2 adrenergic
receptors (β2AR) in T cell to regulate the production of acetylcholine
(ACh), which is catalyzed by choline and acetyl coenzyme A through
choline acetyltransferase (ChAT). ACh is transported into the vesicle by
the vesicle acetylcholine transporter (vAChT) and secreted into the
synaptic space.
(C) ACh binds to α7nAChR on macrophages and α7nAChR is activated,
recruiting Janus kinase 2 (JAK2) to form a heterodimeric complex.
Activating JAK2/signal transducer and activator of transcription 3
(STAT3) pathway, and phosphorylated STAT3 (p-STAT3) reduces nuclear
translocation of nuclear factor kappa-B (NF-κB, p50+p65), p-STAT3 forms
a dimer and transfers to the nucleus, which prevents the production and
release of proinflammatory cytokines. Followed by tyrosine
phosphorylation of phosphatidylinositol kinase (PI3K) and
phosphorylation of protein-serine-threonine kinase (Akt) to activate the
PI3K/Akt pathway, which can reduce apoptosis and toll-like receptor 4
(TLR4) expression. Meanwhile, unphosphorylated STAT3 can also compete
with inhibitor α of NF-κB (IκBα) to bind NF-κB and inhibit TNF
transcriptional activation. Activation of α7nAChR can induce the
production of miRNA, thereby inhibiting STAT3 mRNA translation. α7nAChR
activation can also directly inhibit the inhibitor of nuclear factor
kappa-B kinase (IKKβ) phosphorylation and affect NF-κB pathway. In
addition, α7nAChR activation will down-regulate the mitogen-activated
protein kinase (MAPK) pathway and affect inflammatory factors
transcription. The activation of CAP downregulates the production of
inflammatory factors such as tumor necrosis factor-α (TNF-α),
interleukin-6 (IL-6), interleukin-1β (IL-1β), and high mobility group
box 1 (HMGB1) to achieve the effect of controlling inflammation.