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

Abstract

The α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural α7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis, and the role of the α7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1-50 mM) dosedependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-κB activation. Choline (50 mg/kg, intraperitoneally [i.p.]) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels. In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in α7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from α7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires α7nAChR-mediated signaling.

Acetylcholine Inhibits LPS-Induced MMP-9 Production and Cell Migration via the a7 nAChR-JAK2/STAT3 Pathway in RAW264.7 Cells

“…ACh, the vagal neurotransmitter, attenuated both the early and late phase of LPS-induced TNF-α release in human macrophages [29]. Activation of α7 nAChR attenuates LPS-induced acute lung injuries and improves the survival of mice with sepsis [30,31]. In contrast, vagus nerve stimulation in α7 nAChR-deficient mice failed to reduce serum TNF levels [32].…”

Long-Term Follow-Up of Solitary Intracerebral Juvenile Xanthogranuloma

“…JXG is a non-Langerhans histiocytic infiltrate. The classic finding in JXG is the Touton cell , a multinucleated histiocyte with finely vacuolated, foamy cytoplasm [8,9,10]. The Touton cell is characteristic but not specific for JXG [11].…”

“…Well-developed xanthogranulomas have numerous foamy cells. However, early in the course of the lesion, these may be reduced in number or absent [9, 10, 12]. Histiologic specimens are generally reactive for factor XIII and macrophage markers, including Ki-M1P [9,10,11,12,13].…”

Vagotomy Induces Deregulation of the Inflammatory Response during the Development of Amoebic Liver Abscess in Hamsters

“…Mouse models have demonstrated that the release modulation of TNF-α by inflammatory cells requires cholinergic signaling of α7nAChR [57], as well as NFκB signaling of the transduction of this cytokine [58]. There were high levels of TNF-α in VAG hamsters during the 7 days postinfection.…”