SPLENECTOMY INACTIVATES THE CHOLINERGIC ANTI-INFLAMMATORY PATHWAY DURING LETHAL ENDOTOXEMIA AND POLYMICROBIAL SEPSIS

Abstract

The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver and spleen. The central nervous system regulates innate immune responses via the efferent vagus nerve, a mechanism termed the cholinergic anti-inflammatory pathway. Vagus nerve stimulation inhibits pro-inflammatory cytokine production through a pathway containing the α7 nicotinic acetylcholine receptor. Here we studied the functional relationship between the cholinergic anti-inflammatory pathway and the reticuloendothelial system. Vagus nerve stimulation fails to inhibit systemic TNF production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve also abrogates TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to spleen via this branch of the vagus nerve. Vagus nerve stimulation reduces splenic TNF protein and mRNA levels in wild-type mice, but fails to control splenic TNF levels in α7 knockout mice. Administration of nicotine, an α7 agonist that mimics the anti-inflammatory effects of vagus nerve stimulation and protects against the lethality of polymicrobial sepsis, increases serum HMGB1 levels and worsens survival in splenectomized mice with polymicrobial sepsis, indicating that the critical, α7-dependent anti-inflammatory response requires the spleen. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of α7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury. This study was funded in part by NIGMS and DARPA.