ABSTRACT
Laboratory of Biomedical Science, North Shore-LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030, USA
The innate immune system rapidly responds to bacterial infection, hypotension or haemorrhage with pro-inflammatory cytokines, including TNF, IL-1 and HMGB1, that activate macrophages, monocytes, and neutrophils, initiate tissue repair, and modulate initiate specific cellular immune responses. Failure to control this immune response leads to systemic over-expression of cytokines, which induces diffuse tissue damage, organ failure, and death. Multiple counter-regulatory and anti-inflammatory mechanisms have evolved to confine and regulate innate immune interactions within the site of infection. The central nervous system has a major role in rapidly and directly modulating the immune response. Sensory fibres within the vagus nerve detect peripheral inflammation, and transmit afferent signals that stimulate the release of centrally derived antiinflammatory agents such as ACTH and glucocorticoids, and potentiate anorexia, hyperalgesia and pyrexia. The response to peripheral inflammation also includes antiinflammatory signals carried through motor fibres of the vagus, which terminate in most critical organs. Acetylcholine, the principle neurotransmitter of the vagus, interacts with nicotinic cholinergic receptors expressed on macrophages and other immune cells to inhibit the release of proinflammatory cytokines. This ‘cholinergic anti-inflammatory pathway’ is uniquely positioned to directly and rapidly modulate systemic inflammatory responses.
