Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation

Abstract

Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the α7 nicotinic acetylcholine receptor (α7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the α7 nAChR, we examined the effect of cholinergic stimulation on endothelial cell activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial cell adhesion molecule expression. Using endothelial cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial cell activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor–κB nuclear entry in an inhibitor κB (IκB)α- and IκBɛ-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.

Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

“…In contrast to its suppressive effect on TNF release from endotoxin-stimulated WT peritoneal macrophages, choline did not suppress TNF release from α7nAChR KO cells. These results strengthen the concept that α7nAChR expressed on macrophages and other immune cells plays a critical role in controlling inflammatory responses (4,26).…”

Gestational diabetes and pre-eclampsia: common antecedents?

“…Systemic inflammation with release of inflammatory cytokines has been shown to be associated with insulin resistance and an increased prevalence of gestational diabetes (70)(71)(72)(73). Nicotine has been shown to block the release of inflammatory cytokines, suppressing the phosphorylation of molecules responsible for the inhibition of insulin action through a series of transcriptional events mediated by the NFkB or JNC pathways (74.75), as well as endothelial activation and leukocyte recruitment (76). Thus, cigarette smoking, by inhibiting inflammatory activity linked to insulin resistance, could diminish hyperglycaemia.…”

Autonomic innervation and regulation of the immune system (1987–2007)

“…However, this immune-sensory function of vagal afferents is not unique to the vagus nerve, and all sensory fibers distributed throughout the body, such as skin, muscle, and all mucosal surfaces, can respond to immunological stimuli and transmit this information to the central nervous system. However, studies by Tracey and colleagues (Borovikova et al, 2000;Saeed et al, 2005) have suggested that the efferent vagus nerve, and thus the parasympathetic nervous system, plays a unique and powerful role in regulating systemic and localized inflammatory processes, primarily by inhibiting macrophage production of TNF-α. They have shown that vagal efferent stimulation can inhibit endotoxin-induced sepsis and TNF-α production, as well as localized inflammation induced in a dermal airpouch.…”

“…Among the inflammatory cytokines produced by macrophages, the production and release of the inflammatory cytokine TNF-α is the primary cytokine that is regulated by the sympathetic nervous system. It is of further interest that exactly this same inflammatory cytokine has been the focus of the "cholinerigic anti-inflammatory hypothesis" (Borovikova et al, 2000;Saeed et al, 2005).…”