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.