Reflex Principles of Immunological Homeostasis (Annual Review of Immunology Book 30) by Kevin J. Tracey & Ulf Andersson

Author:Kevin J. Tracey & Ulf Andersson [Tracey, Kevin J.]
Language: eng
Format: mobi
Publisher: Annual Reviews
Published: 2012-11-28T05:00:00+00:00

Endotoxemia

Administration of endotoxin is among the most widely used models for studying the development of therapeutic strategies to inhibit the damaging consequences of uncontrolled innate immunity. Electrical stimulation of the vagus nerve improves survival and selectively reduces systemic and tissue levels of TNF and other proinflammatory cytokines (8, 24). The requirement for α7 nAChR–dependent signaling was also established in this model because vagus nerve stimulation failed to reduce serum TNF levels during endotoxemia in α7 nAChR gene–deficient mice (10). Vagotomy in wild-type mice exposed to toxic doses of endotoxin significantly worsened the severity of disease (8). Protection has been achieved using pharmacological agents that target α7 nAChR, including nicotine and other more selective α7 nAChR agonists (25). Administration of GTS-21 in endotoxemic mice attenuated the release of TNF, macrophage inflammatory protein 2, and keratinocyte-derived cytokine and inhibited neutrophil migration by a cytokine-independent mechanism, suggesting that these agents may confer protection against tissue damage by suppressing the migration of inflammatory cells into tissues (26). A clinical study demonstrated that nicotine administration to human subjects attenuated the inflammatory responses to intravenous endotoxin (27). Other approaches have been to utilize centrally activating agents that target brain circuits to stimulate the cholinergic anti-inflammatory pathway. Agonists of M1 cholinergic receptors, which are expressed in cholinergic brain neurons, can stimulate increased activity in the vagus nerve and inhibit systemic TNF release by this mechanism (28). Indeed, harking back to CNI-1493, the tetravalent guanylhydrazone molecule that led to the discovery of the inflammatory reflex, this molecule later proved to be an agonist of the M1 receptor (6). Thus, intracerebral CNI-1493 stimulates muscarinic brain networks to significantly increase vagus nerve activity and confer significant protection against endotoxin-mediated damage (6).

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