Abstract
Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase+ T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1–60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h in vitro attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.
Highlights
Infection and injury activate immune cells to produce cytokines and other factors that mediate inflammation
To investigate if a single pulse confers a sustained reduction in Tumor Necrosis Factor (TNF) release, mice treated with 0.1 s of vagus nerve stimulation (VNS) were subjected to endotoxemia, 24 h after treatment
The results here indicate that electrical stimulation of the vagus nerve for 0.1–60 s reduces endotoxin-induced TNF release for ≥24 h by a mechanism that requires the α7 nicotinic acetyl choline receptor subunit (α7nAChR) subunit
Summary
Infection and injury activate immune cells to produce cytokines and other factors that mediate inflammation. Macrophage function is critical for protection from infection and injury. Animals rendered deficient in macrophages, or subjected to genetic modifications that prevent cytokine production, have a diminished inflammatory response. The cellular response can be sustained for hours or days. Recent discoveries reveal that the responsiveness of innate immune cells when re-encountering pathogens is modulated by transcription. Inflammatory Reflex Inhibition of TNF factors and epigenetic reprogramming [1]. The mechanisms initiating these changes that regulate inflammation are not fully understood
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