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Finding NEMO mutations

Journal of Experimental Medicine
The Rockefeller University Press
Publication Date
DOI: 10.1084/jem.2037iti3
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JEM_2037iti.indd IN THIS ISSUE 1620 JEM Vol. 203, No. 7, 2006 When confronted with potentially lethal bacterial sepsis, the brain tells the spleen to shut down the production of inflammatory cytokines, according to Huston and colleagues on page 1623. This may help explain why splenectomy renders people more prone to the immunological overreaction of septic shock when infected with certain types of bacteria. When the brain detects inflammation or injury, it sends signals along the vagus nerve—the meandering nerve that regulates vital functions such as heart rate and digestion. This signal triggers the release of the neurotransmitter acetylcholine (Ach) from peripheral nerve endings. Ach then binds to its receptor on immune cells and inhibits the production of inflamma- tory cytokines, in part by inhibiting the activa- tion of the transcription factor NF-κB. This cir- cuit is known as the cholinergic antiinflammatory pathway. Electrical stimulation of the vagus nerve suppresses cytokine production in several rodent models of inflammation. During bacterial sepsis, according to Huston et al., the vagus nerve’s stop signal must be delivered to the spleen, as removing the spleen or severing the branch of the vagus nerve that innervates the spleen abolished the antiinflammatory effect. The spleen produced the bulk of the shock- inducing cytokine TNF in this model, possibly explaining why this organ had to receive the vagus nerve signal. But senior author Kevin Tracey suspects that Ach release always occurs in the spleen, even when the inflammation is happening elsewhere— a hunch they are now testing in an arthritis model. Tracey thinks that vagus nerve signals might educate white blood cells in the spleen, through which circulating cells transit every 2 to 3 min. How immune cells might translate this splenic schooling to inflammation control at distant sites remains to be determined. In the meantime, im- planted pacemaker-like devices that zap the

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