INTRODUCTION AND RATIONALE: The innate immune response is the first line of defense against invading pathogens(1). This tightly regulated system consists of a wide variety of chemokines, cytokines, cell associated receptors and other mediators orchestrating the initial response to infection. Experimental evidence in the past several years has demonstrated that activation of the efferent vagus nerve has an inhibitory effect on the innate immune response (the cholinergic anti-inflammatory pathway, reviewed in (2,3,4)). The anti-inflammatory effect of the vagal nerve is mediated by the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages and other cytokine-producing cells (9). Activation of the cholinergic anti-inflammatory pathway with vagus nerve stimulation or α7nAChR agonists improves outcome in animal models of endotoxemia, sepsis and experimental arthritis. This cholinergic anti-inflammatory pathway is the efferent arm of a reflex mechanism that is activated by inflammatory mediators in peripheral tissues signaling through the afferent vagus nerve. Thus, the vagus nerve can relay inflammation signals to the central nervous system and activate an opposing efferent response to inhibit excessive inflammation.