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Cholinergic control of macrophage activation and functions

Objective

Brain activity can modulate immune responses, but mechanisms involved have remained an enigma. Here, we will substantiate modulation of the innate immune response by the parasympathetic nervous system and evaluate the receptors and signal transduction mechanisms involved.

Excessive inflammation is devastating to tissue and counter-regulatory systems are needed to keep immune responses under control. In a mouse model of intestinal inflammation, we have recently demonstrated that such a mechanism is provided by the cholinergic nervous system. Our data, and that of others, suggest that particularly the vagal nerve, the largest nerve of the body, can reflexively monitor and regulate activation of enteric macrophages (the main class of innate immune cells) via peripheral release of its neurotransmitter acetylcholine. Compared to the classically known regulation of macrophage activation via humoral pathways (i.e. cytokines), neuronal signalling can be rapid, targeted, and directly integrated. This concept is supported by in vivo as well as in vitro data, as acetylcholine negatively regulates macrophage activation via acetylcholine receptors present on these cells.

In the current project we will study which receptors for acetylcholine are involved in the cholinergic nervous systems control of macrophage activation. Cellular responses of macrophages to acetylcholine, and the receptor involved will be determined. We will study which macrophage populations express the acetylcholine receptor, and how these cells respond to agonists of this receptor.

Several acetylcholine receptor agonists are now used to treat neurological disorders. The efficacy of these compounds to regulate inflammatory signalling will be addressed. Also, their efficacy to ameliorate inflammatory disease will be studied in models of enteric inflammation to explore their potential as novel class of anti-inflammatory drugs.

Call for proposal

FP6-2005-MOBILITY-5
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Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Address
University Offices, Wellington Square
PO Box 9600 Oxford
United Kingdom