Huston JM, Ochani M, Rosas-Ballina M, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med 2006;203:1623-8. A research team led by Kevin Tracy at North Shore-LIJ Health System in New York has recently discovered and characterized an anti-inflammatory pathway mediated by acetylcholine (Ach) interactions with specific α7 nicotinic receptors on macrophages. They termed this the “cholinergic anti-inflammatory pathway” and showed that the central nervous system participates by releasing Ach from the efferent vagus nerve. In this paper, they showed that the spleen is the principal recipient of these efferent vagal signals. Utilizing well accepted rodent models of systemic sepsis, they first showed, perhaps surprisingly, that the spleen is the major source of TNF in the blood in systemic sepsis. In response to infusion of lethal doses of endoxin, TNF production in the spleen increased 30-fold, while liver and lung production increased modestly by two- to six-fold. Vagus nerve stimulation decreased splenic TNF production by >90 percent with little or no effect on lung or liver TNF production, and animals that were splenectomized prior to receiving endotoxin had 80 percent less circulating TNF than animals with intact spleens. Furthermore, vagus nerve stimulation did not inhibit systemic TNF production in splenectomized animals or in animals subject to selective vagotomy of the common celiac branches that enervate the spleen. Using genetic knockout mice, they showed that vagus nerve-mediated down-regulation of splenic TNF production and circulating TNF levels required α7 nicotinic receptors and involved both macrophages and splenocytes. The cholinergic anti-inflammatory pathway could be activated pharmacologically as well as by electrical vagal stimulation. Administration of nicotine to mice protected against the lethality of bacterial sepsis or endotoxin infusion. This beneficial result was lost if the mice were splenectomized or if the α7 nicotinic receptor gene was knocked out.
As all practicing hematologists know, severe sepsis syndromes are a significant cause of morbidity and mortality in patients with hematologic malignancies or in patients undergoing hematopoietic progenitor cell transplantation. It is well recognized that uncontrolled cytokine production and release plays a critical role in the pathophysiology of these syndromes. These new studies point to an important role for a “neuro-splenic-immuno axis” in providing counterregulatory anti-inflammaotry signals to blunt the response of the innate immune system to bacterial sepsis. Their work shows that Ach signals mediated by α7 nicotinic receptors on macrophages and splenocytes inhibit activation of the “master” inflammatory transcription factor NF-κB and thereby down-regulate production of potent pro-inflammatory cytokines including TNF. Somehow the brain, via the afferent vagus nerve, senses the presence of potentially lethal sepsis and sends a signal via the efferent vagus nerve to the spleen to shut down production of inflammatory cytokines. Since circulating leukocytes traverse the spleen rapidly and regularly, this mechanism has the capacity to provide systemic “education” to the innate immune system. These studies may explain in part why patients without spleens are more likely to develop sepsis syndromes in the setting of certain bacterial infections. Whether pharmacologic therapy (e.g., nicotine patch) or implanted vagus nerve stimulators can be of benefit in ameliorating or preventing sepsis syndromes is an idea that could be readily tested in clinical trials. The authors provocatively point out that more than 25,000 people have been treated with implantable vagus nerve stimulator devices for intractable seizures without significant complications.
