**4.1 Role of nicotinic receptors**

It is now recognized that there exists a cholinergic anti-inflammatory pathway that acts primarily but not exclusively, through nicotinic acetylcholine receptors. In particular, such pathway has been well characterized in peripheral organs such as spleen where splenic nerve stimulation leads to release of norepinephrine, which in turn, causes release of ACh, where an anti-inflammatory effect is produced [14]. This is because abundant nicotinic (α7 nAChR) are expressed in variety of immune cells including B cells, T cells and macrophages. Activation of these receptors can suppress production of pro-inflammatory cytokines such as TNF- α, IL-1, IL-6 without affecting the anti-inflammatory cytokines such as IL-10. Indeed, several animal models such as sepsis, ischemia–reperfusion, and pancreatitis, which are associated with elevated levels of pro-inflammatory cytokines, show improvement by vagal stimulation. It is believed that this improvement is mediated via activation of α7 nAChRs on macrophages [14, 15]. This contention is further supported by the finding that α7 nAChRs deficient mice show increased endotoxin-induced TNF-α production, which do not respond to electrical vagal stimulation. Because nicotine is a potent activator of nAChRs, including α7 subtype, it was proposed as a potential intervention in control of cytokine storm associated with COVID-19 [11].
