The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity
Introduction
Infection and inflammation characteristically elicit fever and a series of systemic and behavioral responses that collectively are known as the acute-phase response. Fever represents a primary host defense response against the invasion of bacterial and viral pathogens Blatteis and Sehic, 1997, Kluger, 1991. Cytokines, released from antigen-activated immune cells, play a key role as regulators of the host defense response by providing bi-directional signals to the immune system and to the central nervous system (CNS) (Besedovsky and Del Rey, 1996). In fact, the nervous system, alerted by peripherally released cytokines, reacts by producing changes in neural activity that lead to physiological and behavioral responses Besedovsky and Del Rey, 1996, Rothwell and Hopkins, 1995, Schobitz et al., 1994.
Proinflammatory peripheral cytokines can reach and/or stimulate the brain through several pathways: (a) by a specific carrier-mediated transport mechanism (Banks et al., 1995); (b) by binding to cytokine receptors in the endothelial cells of the brain vasculature, where they induce the release of secondary messengers, such as nitric oxide Licinio et al., 1999, Van Dam et al., 1993; (c) acting directly at the circumventricular organs, and other brain areas lacking the blood–brain barrier Blatteis, 1992, Licinio and Wong, 1997, Saper and Breder, 1994; and (d) from immune structures innervated by the peripheral and autonomic nervous systems Felten et al., 1985, Weihe et al., 1999 which transmit afferent information directly to the brain. The latter route may be of particular importance given that its activation can be achieved by amounts of lipopolysaccharide (LPS) or cytokines that produce virtually undetectable levels of blood cytokines Kluger, 1991, Miller et al., 1997.
Over the last few years, experimental evidence has accumulated to support the role of the vagus nerve (X cranial nerve) as the neural pathway transmitting peripheral immune challenges to the brain Ek et al., 1998, Goehler et al., 1997, Goehler et al., 1999, Maier et al., 1998, Niijima, 1996, Simons et al., 1998, Watkins et al., 1995. The vagus nerve contains a high percentage of afferent fibers Berthound et al., 1992, Berthound and Powley, 1993 and bilateral subdiaphragmatic vagotomy, a surgical procedure that disrupts both afferent and efferent innervation of the abdominal cavity, has been employed as an experimental paradigm to examine the role of vagal transmission of peripheral immune signals to the brain. In several recent studies, subdiaphragmatic vagotomy has been shown to block or at least attenuate brain-mediated responses to peripheral immune challenge induced by intraperitoneal (i.p.) or intravenous (i.v.) injections of lipopolysacharide (LPS) or interleukin (IL)-1β Bluthe et al., 1994, Fleshner et al., 1998, Gaykema et al., 1995, Hansen and Krueger, 1997, Hansen et al., 1998, Laye et al., 1995, Opp and Toth, 1998, Romanovsky et al., 1997, Simons et al., 1998, Watkins et al., 1995. However, it should be noted that the effects of subdiaphragmatic vagotomy may be restricted to the abdominal cavity. Sectioning the vagus at its upper levels in order to disrupt the afferent input of the entire nerve would be preferable but transection of the vagus above thoracic levels is fatal. Despite the critical role of the vagus in immune-to-brain communication, other neural routes linking peripheral cytokines and brain are conceivable. For instance, subcutaneous injections of IL-1β into the plantar skin of the hindpaw has been found to induce spontaneous activation of cutaneous nerves (Fukuoka et al., 1994), while tumor necrosis factor-α (TNF-α) directly applied to the sciatic nerve induces ectopic activity (Sorkin et al., 1997). In addition, a low dose of LPS, injected into a subcutaneous chamber after anesthetic pretreatment, attenuated the fever response in guinea pigs, suggesting a role for cutaneous nerves in immune-to-brain communication (Ross et al., 1999).
A neural route that has been overlooked and therefore has not been investigated as another pathway in immune-to-brain communication is the glossopharyngeal (IX cranial nerve). The rat glossopharyngeal is a mixed nerve that mainly comprises afferent (sensory) fibers and provides innervation for the parotid gland, posterior one-third of the tongue, soft palate and the pharynx (Altschuler et al., 1989). Indeed, the posterior oral cavity, with its glossopharyngeal-innervated mucosal-associated lymphoid tissues (Weihe et al., 1999), is located in the front line of defense against potential infections.
Our hypothesis is that the glossopharyngeal nerve plays a key role in immune-to-brain communication from the posterior oral cavity. We anticipate that bilateral transection of the glossopharyngeal nerves will disrupt this communication by blocking or attenuating the acute-phase response induced by local immune challenges of the posterior oral cavity. Fever, as the most manifest sign of the acute-phase response to infection and inflammation, is observable following administration of LPS and IL-1β. Thus, in order to test our hypothesis, we investigated the effects of a bilateral surgical transection of the glossopharyngeal nerve on the LPS- and IL-1β-induced febrile response recorded with biotelemetric measurements of body temperature.
Section snippets
Subjects
Male Sprague–Dawley rats from Charles River Breeding Labs (Portage, MI), weighing 320–350 g at the start of the experiments, were used in all the studies. Upon arrival, rats were acclimated for 1 week to our standard temperature and light conditions (22±1°C, 14/10 h light cycle: 0600–2000 h). Food (pellet rat chow, Harlan, WI) and water were provided ad libitum. All experimental procedures were approved by the UCLA and VA institutional animal care and use committees.
Substances
Purified LPS (Escherichia
Experiment 1: febrile response to varying doses of LPS injected ISP in intact rats
LPS injections into the soft palate of intact rats began to produce fever at 120 min after injection, and fever subsided around 480 min post-injection (Fig. 1). Repeated measures ANOVA of the differences between temperatures recorded at comparable time-points after LPS and saline for the hyperthermic period (120–480 min) indicated a significant effect of dose [F(2,14)=4.08, p=0.04]. The mean±S.E.M. average total responses for this period to 25, 50 and 100 μg/kg were: −0.064±0.109°C,
Discussion
In the present study, we have provided experimental support for our hypothesis that postulates the glossopharyngeal nerve as a novel neural route for immune-to-brain communication. Our demonstration that bilateral surgical transection of the glossopharyngeal nerve attenuates the LPS- or IL-1β-induced febrile component of the acute-phase response is evidence for disruption of immune-to-brain communication by this route. The soft palate was selected as the anatomical site for experimental immune
Acknowledgements
The helpful discussions on electrophysiological aspects of the glossopharyngeal nerve with Dr. Oscar U. Scremin and on statistical analyses with Dr. Jeffrey A. Gornbein are gratefully acknowledged. We also thank Terrill T.-L. Tang for technical assistance. Supported by grants from the NIH/NIAAA (AA09850), the Department of Veterans Affairs Medical Research Service, and the Norman Cousins Center for Psychoneuroimmunology in the Neuropsychiatric Institute at UCLA.
References (53)
Role of the OVLT in the febrile response to circulating pyrogens
Prog. Brain Res.
(1992)- et al.
Thermogenic and corticosterone responses to intravenous cytokines (IL-1β and TNF-α) are attenuated by subdiaphragmatic vagotomy
J. Neuroimmunol.
(1998) - et al.
Cutaneous hyperalgesia induced by peripheral injection of interleukin-1β in the rat
Brain Res.
(1994) - et al.
Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: a possible mechanism for immune-to-brain communication
Brain Res. Bull.
(1997) - et al.
Axotomy alters putative neurotransmitters in visceral sensory neurons of the nodose and petrosal ganglia
Brain Res.
(1991) - et al.
Specific postoperative syndromes after total and selective vagotomies in the rat
Appetite
(1986) - et al.
Brain iNOS: current understanding and clinical implications
Mol. Med. Today
(1999) The afferent discharges from sensors for interleukin-1β in the hepatoportal system in the anesthetized rat
J. Auton. Nerv. Syst.
(1996)- et al.
Somnogenic and pyrogenic effects of interleukin-1β and lypopolysaccharide in intact and vagotomized rats
Life Sci.
(1998) - et al.
Effects of selective vagotomies on knife cut-induced hypothalamic obesity: differential results on lab-chow vs. high-fat diets
Physiol. Behav.
(1981)
Gene expression and function of interleukin 1, interleukin 6 and tumor necrosis factor in the brain
Prog. Neurobiol.
Tumour necrosis factor-α induces ectopic activity in nociceptive primary afferent fibres
Neuroscience
Immunocytochemical detection of prostaglandin E2 in microvasculature and in neurons of rat brain after administration of bacterial endotoxin
Brain Res.
Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune–brain communication
Neurosci. Lett.
The neuroimmune connection in human tonsils
Brain Behav. Immun.
Effects of fetal alcohol exposure on fever, sickness behavior and pituitary–adrenal activation induced by interleukin-1β in young adult rats
Brain Behav. Immun.
Vicerotopic representation of the upper alimentary tract in the rat: sensory ganglia and nuclei of the solitary and spinal trigeminal tracts
J. Comp. Neurol.
Permeability of the blood–brain barrier to soluble cytokine receptors
Neuroimmunomodulation
Characterization of vagal innervation to the rat celiac, suprarenal and mesenteric ganglia
J. Auton. Nerv. Syst.
An anterograde tracing study of the vagal innervation of rat liver, portal vein and biliary system
Anat. Embryol.
Immune–neuro-endocrine interactions: facts and hypotheses
Endocr. Rev.
Fever; how might circulating pyrogens signal the brain?
News Physiol. Sci.
Lypopolysaccharide induces sickness behavior in rats by a vagal mediated mechanism
C. R. Acad Sci. III
Stress hyperthermia: physiological arguments that it is a fever
Physiol. Behav.
Effects of anesthesia with halothane and methoxyflurane on plasma corticosterone concentrations in rats at rest and after exercise
Lab. Anim. Sci.
Humoral versus neural pathways for fever production in rats after administration of lipopolysaccharide
J. Trauma
Cited by (96)
Inflammation and Behavior Changes in Dogs and Cats
2024, Veterinary Clinics of North America - Small Animal PracticeSystemic inflammatory regulators and 7 major psychiatric disorders: A two-sample Mendelian randomization study
2022, Progress in Neuro-Psychopharmacology and Biological PsychiatryAdolescent neuroimmune function and its interaction with alcohol
2022, International Review of NeurobiologySystemic LPS-induced microglial activation results in increased GABAergic tone: A mechanism of protection against neuroinflammation in the medial prefrontal cortex in mice
2022, Brain, Behavior, and ImmunityCitation Excerpt :Moreover, our results support the notion that microglia in different brain regions, or across different developmental or pathogenic phases, may rely on different signaling mechanisms to perform their various functions. It is worth noting that IP injection of LPS can cause macrophage activation and inflammation in the peritoneum that is propagated to the brain through neuroimmune pathways, such as the vagus nerve and cytokines in the blood (Bode et al., 2012; Goehler et al., 1999; Romeo et al., 2001; Watkins et al., 1995). Therefore, changes in neuronal function observed in this study may be regulated by pathways independent of local microglia activation, limiting interpretation of studies that used bath application of LPS on brain slices.
An immune gate of depression – Early neuroimmune development in the formation of the underlying depressive disorder
2019, Pharmacological Reports