Abstract
The inflammatory reflex is a neural circuit that regulates innate immune responses to endotoxin and other stimulating agents. It confers protection against damaging inflammation by ...inhibiting synthesis and release of TNF and other cytokines. Action potentials transmitted in the vagus nerve stimulate acetylcholine release, a neurotransmitter which inhibits cytokine production by interacting with a7nAChR expressed on macrophages and other cytokine-producing cells. We studied the effects of electrical stimulation of the vagus nerve, and observed that a brief period of neural stimulation resulted in suppression of TNF release that persisted for several days. To deconvolute this effect, we implanted vagus nerve stimulators in ambulatory canines, and found that brief electrical pulses significantly inhibited endotoxin-induced TNF release for up to 9 days. Exposure of isolated monocytes and macrophages to acetylcholine reduced TNF production for 24 h via signal transduction through a7nAChR. a7nAChR interaction with type 6 adenylate cylcase upregulated cAMP levels, and enhanced phosphorylation of CREB. Transfection of monocytes with a dominant negative CREB blocked the prolonged deactivation of monocytes exposed transiently to acetylcholine or a7nAChR agonists. Thus, signals originating as action potentials in the vagus nerve produce an a7nAChR - CREB dependent deactivated phenotype in monocytes, which has significant implications for understanding the regulation of innate immunity.
Abstract
Low-grade systemic inflammation is a central event in obesity and mediates insulin resistance and other complications. Previously we discovered a role for neural cholinergic signaling in ...controlling inflammation (Nature, 2000, 405, 6785; Proc Natl Acad Sci USA, 2006, 5219) and demonstrated that the acetylcholinesterase inhibitor galantamine suppresses systemic lethal inflammation (Brain Behav Immun, 2009, 4; 1). Here we tested the efficacy of galantamine in alleviating obesity-associated inflammation. C57BL/6J mice with high fat-diet induced (for 8 weeks) obesity were treated with either galantamine (4 mg/kg daily, i.p.), or saline for 4 weeks while on the high-fat diet. Galantamine treatment of obese mice resulted in lower body weight and abdominal adiposity as compared to saline treatment. Galantamine significantly decreased systemic levels of characteristic pro-inflammatory cytokines/adipokines, including IL-6, MCP-1, resistin and leptin and increased adiponectin levels, accompanied by alleviated hyperglycemia, hyperinsulinemia, insulin resistance and hepatosteatosis. These results demonstrate that galantamine reduces obesity-associated inflammation and alleviates obesity-related complications and provide a rationale for further mechanistic studies and novel therapeutic implications. Translational aspects of these studies will be additionally facilitated by the fact that galantamine is a FDA approved (for the treatment of Alzheimer’s disease) cholinergic agent.
Abstract
The central nervous system regulates innate immunity reflexively, as action potentials transmitted in the vagus nerve suppress cytokine release during endotoxemia. The mechanism of cytokine ...release by this neural circuit requires signaling through the alpha 7 nicotinic acetylcholine receptor (a7 nAChR), but the duration of this protection is incompletely understood. Electrical vagus nerve stimulation (VNS) in mice significantly inhibited serum TNF levels during endotoxemia, even when endotoxin was given 2, 24 or 48 h after VNS. This inhibition of TNF was abolished in a7 nAChR deficient mice, confirming the mechanism that requires this receptor. One-hour exposure of human macrophages to acetylcholine in vitro reduced endotoxin-induced increases in IKKbeta, IkappaBalpha activity and TNF release for up to 24 h after removal of acetylcholine. Levels of Supressor of Cytokine Signaling 1-3, A20, BCL3, IkappaBNS and IkappaBzeta were not altered in human macrophages 15 min to 8 h after exposure to acetylcholine, but exposure of macrophages to the selective JAK/STAT inhibitor AG490 abolished the cytokine suppressing effect of acetylcholine. Together with previous work indicating that JAK/STAT forms a signaling complex with a7 nAChR, these results suggest that JAK/STAT activation is required for long lasting suppression of macrophage cytokine release after transient exposure to acetylcholine.
Our main aims were to establish criteria for early distinction between meningococcal disease and other conditions with similar clinical features, and to identify other causes of haemorrhagic rashes ...accompanied by fever.
This prospective study comprised 264 infants and children hospitalised with fever and skin haemorrhages.
We identified an aetiological agent in 28%: 15% had meningococcal disease, 2% another invasive bacterial infection, 7% enterovirus infection, and 4% adenovirus infection. Five clinical variables discriminated meningococcal disease from other conditions on admission: skin haemorrhages of (1) characteristic appearance; (2) universal distribution and (3) a maximum diameter of > 2 mm; (4) poor general condition; and (5) nuchal rigidity.
If any two or more of these clinical variables were present, the probability of identifying a patient with meningococcal disease was 97% and the false-positive rate was only 12%. This diagnostic algorithm did not identify children in whom septicaemia was caused by other bacterial species.
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