The effect of pro-inflammatory cytokines on the discharge rate of vagal nerve paraganglia in the rat (original) (raw)
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Cytokine-specific Neurograms in the Sensory Vagus Nerve
Bioelectronic Medicine
The vagus nerve is primarily sensory, and it is the principal conduit that relays afferent signals from the visceral organs to the brainstem. Seminal studies by Linda Watkins revealed that an intact vagus nerve is required for the development of pyrexia in response to intra-abdominal IL-1β administration (4,5). Moreover, early work by Niijima (6-8) suggested that IL-1β might activate signaling in peripheral vagus afferents. Sensory neurons express cytokine receptors, including TNF and IL-1β receptors, and change their activation thresholds when exposed to the corresponding cytokines (9-11). This work, together with other studies, suggests that the vagus nerve may be an important component of a peripheral neural network capable of reporting changes in peripheral inflammation and immunity. Here we reasoned that the vagus nerve transmits specific neural signatures in response to specific cytokines. immune responses. A prototypical neural pathway is the inflammatory reflex (1), defined by the electrical signals transmitted in the vagus nerve to the splenic nerve, culminating in a specialized subset of T lymphocytes that release acetylcholine (2,3). This T cell-derived neurotransmitter signals via a mechanism that depends on α-7 nicotinic acetylcholine receptors (α-7nAChR) to inhibit cytokine production by splenic macrophages (2).
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Intraperitoneal administration of the cytokine interleukin-1 (IL-1) induces brain-mediated sickness symptoms that can be blocked by subdiaphragmatic vagotomy. Intraperitoneal IL-1 also induces expression of the activation marker c-fos in vagal primary afferent neurons, suggesting that IL-1 is a key component of vagally mediated immune-to-brain communication.
Peripheral nerve fibroblasts as a source of IL-6, TNFα and IL-1 and their modulation by IFNγ
Journal of the Neurological Sciences, 1998
Interleukin-6 (IL-6), tumor necrosis factor alpha (TNFa), and interleukin-1 (IL-1) are immunomodulatory cytokines produced by Schwann cells of the peripheral nervous system (PNS). Their upregulation has been associated with autoimmune inflammatory diseases of the PNS such as Guillain-Barre Syndrome (GBS) and Chronic Inflammatory Demyelinating Neuropathy (CIDP). We now report that PNS fibroblasts and a PNS fibroblast cell line -MA-1 express mRNA for IL-6, TNFa and IL-1 and that the MA-1 cell line secretes these 1 molecules. Flow cytometry and fluorescent activated cell sorting defined that 76% of MA-1 fibroblasts were Thy1.1 and 24% were 2 Thy1.1 . Each subset expressed major histocompatibility class (MHC) I molecules and intercellular adhesion molecule-1 (ICAM-1).
Neural modulation of inflammation
2013
The impact of an immune response on the nervous system has long been apparent; however, the influence of the nervous system on immune responses is not well understood. The complex characters of a coordinated immune response of the body complicate research in this area. Any entity would be compromised if its defence and communication systems did not interact-humans are no exception. This study aims to highlight the role of muscarinic receptors (M1 and M2) in modulating inflammation via the use of Bethanechol chloride in rat model. It is a directly acting cholinergic receptor stimulant with predominant muscarinic agonistic activity. By increasing the tone of parasympathetic nervous system and stimulating receptors on macrophages, Bethanechol, like other choline esters, is expected to have an anti-inflammatory response. [1] A dual relationship exists between inflammatory process and nervous system and this has been studied using different animal models. [2] The signs of inflammation like vasodilation and plasma extravasation were elicited by stimulation of nerves. However, in our study, we attempt to understand the extent of autologous nature of the immune system. The inflammatory stimulus is introduced and neuronal activity is totally blocked with local anaesthetic and compared with controls for signs of inflammation, thus eliciting the extent of autologous nature of immune system. MATERIALS AND METHODS: ABSTRACT Background: In the present situation of emerging cases of drug allergies, auto-immune disorders and adverse reactions to anti-inflammatory drugs, there is a need to find an alternative for handling abnormal immune status which causes inflammatory storm. There is a growing need to exploit the nervous system for understanding the role played by neurons in the inflammatory process. Aims and objectives: The purpose of this study was to understand the anti-inflammatory role of parasympathetic nervous system using Bethanechol chloride and to study the contribution of neurons in modulating inflammation using 2% Carrageenan. Materials and methods: Thirty female Wistar (WNIN) rats were selected for this study. Twenty five WNIN rats, divided into five groups were selected for studying the anti-inflammatory activity of Bethanechol chloride. The remaining five rats were selected to elicit the interdependent natures of immune and nervous systems. 2% Carrageenan was injected in both the hind paws. In both the study protocols, increase in paw volume was measured using plethysmometer and subjected to calculations. Results: A significant anti-inflammatory activity of Bethanechol chloride compared to control group was observed. In the other part of study, the right paw, in which Carrageenan reconstituted in Lidocaine was injected, showed nearly no signs of inflammation in the initial hours, while left paw injected with Carrageenan dissolved in distilled water presented with a typical Carrageenan-induced paw oedema. However, one to two hours later (which corresponds to the half-life of Lidocaine), the right paw also showed the same degree of oedema. Conclusion: We conclude that Bethanechol chloride has anti-inflammatory activity at small doses, and therefore can be used as an adjuvant in the treatment of chronic inflammatory disorders. This study also shows that immune system works in conjunction with the nervous system in modulating inflammation.
Immunocytes modulate ganglionic nitric oxide release which later affects their activity level
PubMed, 2004
Pedal ganglia excised and maintained in culture for up to 2 h, release NO at low levels. The range can vary between 0 to 1.1 nM. Non-stimulated immunocytes do not significantly stimulate ganglionic NO release when incubated with pedal ganglia. However, ganglia exposed to immunocytes that had been previously activated by a 30 min incubation with interleukin 1 beta, release NO significantly above basal levels. In these experiments, 91 +/- 2.5% of the non-stimulated immunocytes exhibited form factors in the 0.72 to 0.89 range (sampled prior to ganglionic addition), whereas 62 +/- 10.3% of the interleukin 1 beta stimulated immunocytes had form factors in the 0.39 to 0.49 range, demonstrating activation. Addition of the nitric oxide synthase inhibitor, L-NAME (10(-4) M), inhibited basal ganglionic NO release as well as that initiated by exposing the ganglia to activated immunocytes. Interestingly, non activated immunocytes, following ganglionic exposure, exhibited activity levels in the 13% range, representing a non significant increase. Cells exposed to interleukin 1 beta had a 65% activity level at the beginning of the experiment, followed by a drop of activity to 19 +/- 3.2% after ganglionic exposure. Repeating this last observation in the presence of L-NAME (10(-4) M), brought the activity level of the immunocytes back to the pre-ganglionic exposure level of activity, demonstrating that ganglionic NO was involved in down regulating immunocyte activity.
Pedal ganglia excised and maintained in culture for up to 2 h, release NO at low levels. The range can vary between 0 to 1.1 nM. Non-stimulated immunocytes do not significantly stimulate ganglionic NO release when incubated with pedal ganglia. However, ganglia exposed to immunocytes that had been previously activated by a 30 min incubation with interleukein1β, release NO significantly above basal levels. In these experiments, 91 ± 2.5% of the non-stimulated immunocytes exhibited form factors in the 0.72 to 0.89 range (sampled prior to ganglionic addition), whereas 62 ± 10.3% of the interleukin 1β stimulated immunocytes had form factors in the 0.39 to 0.49 range, demonstrating activa- tion. Addition of the nitric oxide synthase inhibitor, L-NAME (10-4 M), inhib- ited basal ganglionic NO release as well as that initiated by exposing the ganglia to activated immunocytes. Interestingly, non activated immunocytes, following ganglionic exposure, exhibited activity levels in the 13% range,...
Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity
Proceedings of the National Academy of Sciences
The nervous system maintains physiological homeostasis through reflex pathways that modulate organ function. This process begins when changes in the internal milieu (e.g., blood pressure, temperature, or pH) activate visceral sensory neurons that transmit action potentials along the vagus nerve to the brainstem. IL-1β and TNF, inflammatory cytokines produced by immune cells during infection and injury, and other inflammatory mediators have been implicated in activating sensory action potentials in the vagus nerve. However, it remains unclear whether neural responses encode cytokine-specific information. Here we develop methods to isolate and decode specific neural signals to discriminate between two different cytokines. Nerve impulses recorded from the vagus nerve of mice exposed to IL-1β and TNF were sorted into groups based on their shape and amplitude, and their respective firing rates were computed. This revealed sensory neural groups responding specifically to TNF and IL-1β in ...
Brain Research, 2004
Tumor necrosis factor alpha (TNF a ) is a potent modulator of autonomic reflex mechanisms that control the stomach. Evidence suggests that TNF a action directly on vago-vagal reflex control circuits causes the autonomic misregulation of digestion manifested as gastrointestinal stasis, nausea, and emesis associated with illness. Neurophysiological studies indicated that TNF a may have effects on vagal afferents in the solitary nucleus, as well as neurons of the solitary nucleus (NST) and dorsal motor nucleus (DMN) of the vagus. The aim of this study was to determine the location of the TNFR1 receptor (p55) in the medulla using immunocytochemical methods. We devised a technique for localizing the p55 receptor using heat-induced antigen recovery in fixed tissue sections. This protocol allowed us to demonstrate that dense p55-immunoreactivity (p55-ir) is constitutively present on central (but not peripheral) vagal afferents in the solitary tract (ST) and nucleus; p55-ir is also present on afferents entering the spinal trigeminal nucleus. Unilateral supra-nodose vagotomy eliminated p55-ir from ipsilateral central vagal afferents. Virtually all neurons in the brainstem appeared to express p55-ir at a low level, i.e., just above background. However, vagotomy caused a dramatic up-regulation of p55-ir in vagal motor neurons. This increase in p55-ir in axotomized neurons may play a pivotal role in the connection between the occurrence of the injury and the initiation of apoptotic processes resulting in elimination of damaged neurons. D
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Intravenous administration of interleukin-1 (IL-1) activates central autonomic neuronal circuitries originating in the nucleus of the solitary tract (NTS). The mechanism(s) by which bloodborne IL-1 regulates brain functions, whether by operating across the blood-brain barrier and/or by activating peripheral sensory afferents, remains to be characterized. It has been proposed that vagal afferents originating in the periphery may monitor circulating IL-1 levels, because neurons within the NTS are primary recipients of sensory information from the vagus nerve and also exhibit exquisite sensitivity to blood-borne IL-1. In this study, we present evidence that viscerosensory afferents of the vagus nerve respond to intravenously administered IL-1. Specific labeling for mRNAs encoding the type 1 IL-1 receptor and the EP3 subtype of the prostaglandin E2 receptor was detected in situ over neuronal cell bodies in the rat nodose ganglion. Moreover, intravenously applied IL-1 increased the number of sensory neurons in the nodose ganglion that express the cellular activation marker c-Fos, which was matched by an increase in discharge activity of vagal afferents arising from gastric compartments. This response to IL-1 administration was attenuated in animals pretreated with the cyclooxygenase inhibitor indomethacin, suggesting partial mediation by prostaglandins. In conclusion, these results demonstrate that somata and/or fibers of sensory neurons of the vagus nerve express receptors to IL-1 and prostaglandin E2 and that circulating IL-1 stimulates vagal sensory activity via both prostaglandindependent and -independent mechanisms.