Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

Abstract

The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit ␣7, a mechanism termed ''the cholinergic antiinflammatory pathway.'' Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of ␣7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiacsuperior mesenteric plexus, and projecting in the splenic nerve.brain ͉ cytokine ͉ innate ͉ spleen ͉ vagus T he autonomic nervous system is divided into two major branches based on anatomy and function. These divisions, sympathetic and parasympathetic, control organ function through a set of two serially connected neurons, the first of which is located in the CNS and the second in the peripheral ganglia. Typically, parasympathetic neurons originate in the brainstem medulla and sacral portion of the spinal cord, and the ganglia are located close to or within the innervated organ. Sympathetic neurons originate in the thoracic and lumbar portion of the spinal cord, and the ganglia are situated close to the spinal cord.

Neural Signaling in the Spleen Controls B-Cell Responses to Blood-Borne Antigen

“…To demonstrate directly the neural mechanism for regulating migratory arrest, we next assessed cell trafficking following direct electrical stimulation of the vagus nerve, using methods that we have developed and described previously (30). We observed that vagus nerve stimulation arrested the transit of cells from the MZ significantly ( Figures 4A-B).…”

“…The cholinergic antiinflammatory pathway is a two neuron circuit (30). Action potentials originating in the vagus nerve propagate to and terminate at the celiac ganglion, where the cell bodies of the postganglionic secondary neurons reside.…”

Ultrasound Modulates the Splenic Neuroimmune Axis in Attenuating AKI

“…14 To explore the role of this input in splenic modulation of AKI, the spleen was chemically denervated by locally injecting 6-hydroxydopamine (6-OHDA), a neurotoxin that destroys catecholaminergic neurons. 15 Similar to splenectomy, splenic 6-OHDA, as little as 15 mg injected 14 days before subIRI, exacerbated kidney injury as shown by increased plasma creatinine (P,0.001) and acute tubular necrosis compared with mice with splenic vehicle (saline) injections before subIRI ( Figure 3).…”

The shock tactics set to shake up immunology

“…They tried cutting the nerve in different places 4 and using drugs that block specific neurotransmitters 5 . These experiments seemed to show that when the vagus is zapped with electricity, a signal pulses down it into the abdomen, and then through a second nerve into the spleen.…”