Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent?


      The first studies carried out on the mechanisms by which peripheral immune stimuli signal the brain to induce fever, activation of the hypothalamic–pituitary–adrenal axis and sickness behavior emphasized the importance of fenestrated parts of the blood–brain barrier known as circumventricular organs for allowing blood-borne proinflammatory cytokines to act on brain functions. The discovery in the mid-1990s that subdiaphragmatic section of the vagus nerves attenuates the brain effects of systemic cytokines, together with the demonstration of an inducible brain cytokine compartment shifted the attention from circumventricular organs to neural pathways in the transmission of the immune message to the brain. Since then, neuroanatomical studies have confirmed the existence of a fast route of communication from the immune system to the brain via the vagus nerves. This neural pathway is complemented by a humoral pathway that involves cytokines produced at the level of the circumventricular organs and the choroid plexus and at the origin of a second wave of cytokines produced in the brain parenchyma. Depending on their source, these locally produced cytokines can either activate neurons that project to specific brain areas or diffuse by volume transmission into the brain parenchyma to reach their targets. Activation of neurons by cytokines can be direct or indirect, via prostaglandins. The way the neural pathway of transmission interacts with the humoral pathway remains to be elucidated.


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        • Agnati L.F.
        • Zoli M.
        • Strömberg I.
        • Fuxe K.
        Intercellular communication in the brain: wiring versus volume transmission.
        Neuroscience. 1995; 69: 711-726
        • Andreis P.G.
        • Neri G.
        • Belloni A.S.
        • Giuseppina M.
        • Kasprzak A.
        • Nussdorfer L.G.G.
        Interleukin-1β enhances corticosterone secretion by acting directly on the rat adrenal gland.
        Endocrinology. 1991; 129: 53-57
        • Anika S.M.
        • Houpt T.R.
        • Houpt K.A.
        Satiety elicited by cholecystokinin in intact and vagotomized rats.
        Physiol. Behav. 1977; 19: 761-766
        • Ban E.
        • Haour F.
        • Lenstra R.
        Brain interleukin 1 gene expression induced by peripheral lipopolysaccharide administration.
        Cytokine. 1992; 4: 48-54
        • Banks W.A.
        • Kastin A.J.
        Blood-to-brain transport of interleukins links the immune and central nervous systems.
        Life Sci. 1991; 48: 117-121
        • Berthoud H.R.
        • Kressel M.
        • Neuhuber W.L.
        An anterograde tracing study of the vagal innervation of rat liver, portal vein and biliary system.
        Anat. Embryol. (Berl.). 1992; 186: 431-442
        • Blatteis C.M.
        Role of the OVLT in the febrile response to circulating pyrogens.
        Prog. Brain Res. 1992; 91: 409-412
        • Bluthé R.M.
        • Michaud B.
        • Kelley K.W.
        • Dantzer R.
        Vagotomy blocks behavioural effects of interleukin-1 injected peripherally but not centrally.
        NeuroReport. 1996; 7: 1485-1488
        • Bluthé R.M.
        • Michaud B.
        • Kelley K.W.
        • Dantzer R.
        Vagotomy blocks behavioural effects of interleukin-1 injected via the intraperitoneal route but not via other systemic routes.
        NeuroReport. 1996; 7: 2823-2827
        • Bluthé R.M.
        • Walter V.
        • Parnet P.
        • Layé S.
        • Lestage J.
        • Verrier D.
        • Poole S.
        • Stenning B.E.
        • Kelley K.W.
        • Dantzer R.
        Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism.
        C.R. Acad. Sci. Paris, Sér. III. 1994; 317: 499-503
        • Brady L.S.
        • Lynn A.B.
        • Herkenham M.
        • Gottesfeld Z.
        Systemic interleukin-1 induces early and late patterns of c-fos mRNA expression in brain.
        J. Neurosci. 1994; 14: 4951-4964
        • Breder C.D.
        • Hazuka C.
        • Ghayur T.
        • Klug C.
        • Huginin M.
        • Yasuda K.
        • Teng M.
        • Saper C.B.
        Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration.
        Proc. Natl. Acad. Sci. USA. 1994; 91: 11393-11397
        • Bret-Dibat J.L.
        • Bluthé R.M.
        • Kent S.
        • Kelley K.W.
        • Dantzer R.
        Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism.
        Brain Behav. Immunol. 1995; 9: 242-246
        • Buckinskaite V.
        • Kurosawa M.
        • Miyasaka A.
        • Funakoshi A.
        • Lundeberg T.
        Interleukin-1β sensitizes the response of the gastric vagal afferent to cholecystokinin in rat.
        Neurosci. Lett. 1997; 229: 33-36
        • Buttini M.
        • Boddeke H.
        Peripheral lipopolysaccharide stimulation induces interleukin-1 beta messenger RNA in rat brain microglial cells.
        Neuroscience. 1995; 65: 523-530
        • Cao C.
        • Matsumura K.
        • Yamagata K.
        • Watanabe Y.
        Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever.
        Brain Res. 1996; 733: 263-272
        • Cunningham E.T.
        • De Souza E.B.
        Interleukin-1 receptors in the brain and endocrine tissues.
        Immunol. Today. 1993; 14: 171-176
        • Dantzer R.
        How do cytokines say hello to the brain? Neural versus humoral mediation.
        Eur. Cytokine Netw. 1994; 5: 271-273
        • Dantzer R.
        • Bluthé R.M.
        • Layé S.
        • Bret-Dibat J.L.
        • Parnet P.
        • Kelley K.W.
        Cytokines and sickness behavior.
        Ann. N.Y. Acad. Sci. 1998; 840: 586-590
        • Elmquist J.K.
        • Scammell T.E.
        • Jacobson C.D.
        • Saper C.B.
        Distribution of Fos-like immunoreactivity in the rat brain following intravenous lipopolysaccharide administration.
        J. Comp. Neurol. 1996; 371: 85-103
        • Ericsson A.
        • Kovacs K.J.
        • Sawchenko P.E.
        A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons.
        J. Neurosci. 1994; 14: 897-913
        • Ericsson A.
        • Liu C.
        • Hart R.P.
        • Sawchenko P.E.
        Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1-induced cellular activation.
        J. Comp. Neurol. 1995; 361: 681-698
        • Gatti S.
        • Bartfai T.
        Induction of tumor necrosis factor-alpha mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6.
        Brain Res. 1993; 624: 291-294
        • Gaykema R.P.A.
        • Dijkstra I.
        • Tilders F.J.H.
        Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion.
        Endocrinology. 1995; 136: 4717-4770
        • Goehler L.E.
        • Gaykema R.A.
        • Nguyen K.T.
        • Lee J.E.
        • Tilders F.J.H.
        • Maier S.F.
        • Watkins L.R.
        Interleukin-1β in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems?.
        J. Neurosci. 1999; 19: 2799-2806
        • Goldbach J.M.
        • Roth J.
        • Zeisberger E.
        Fever suppression by subdiaphragmatic vagotomy in guinea pigs depends on the route of pyrogen administration.
        Am. J. Physiol. 1997; 272: R675-R681
        • Hansen M.K.
        • Taishi P.
        • Chen Z.
        • Krueger J.M.
        Vagotomy blocks the induction of interleukin-1β (IL-1β) mRNA in the brain of rats in response to systemic IL-1β.
        J. Neurosci. 1998; 18: 2247-2253
        • Hare A.S.
        • Clarke G.
        • Tolchard S.
        Bacterial lipopolysaccharide-induced changes in FOS protein expression in the rat brain: correlation with thermoregulatory changes and plasma corticosterone.
        J. Neuroendocrinol. 1995; 7: 791-799
        • Hart B.L.
        Biological basis of the behavior of sick animals.
        Neurosci. Biobehav. Rev. 1988; 12: 123-137
        • Herkenham M.
        • Lee H.Y.
        • Baker R.A.
        Temporal and spatial patterns of c-fos mRNA induced by intravenous interleukin-1: a cascade of non-neuronal cellular activation at the blood–brain barrier.
        J. Comp. Neurol. 1998; 400: 175-196
        • Kapcala L.P.
        • He J.R.
        • Gao Y.
        • Pieper J.O.
        • DeTolla L.J.
        Subdiaphragmatic vagotomy inhibits intra-abdominal interleukin-1β stimulation of adrenocorticotropin secretion.
        Brain Res. 1996; 728: 247-254
        • Kent S.
        • Bluthé R.M.
        • Dantzer R.
        • Hardwick A.J.
        • Kelley K.W.
        • Rothwell N.J.
        • Vannice J.L.
        Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin-1.
        Proc. Natl. Acad. Sci. USA. 1992; 89: 9117-9120
        • Kent S.
        • Bluthé R.M.
        • Kelley K.W.
        • Dantzer R.
        Sickness behavior as a new target for drug development.
        Trends Pharmacol. Sci. 1992; 13: 24-28
      1. Konsman, J.P., 1999. Immune-to-brain communication: a functional neuroanatomical approach. PhD Thesis, University of Gröningen and University of Bordeaux II.

        • Konsman J.P.
        • Kelley K.W.
        • Dantzer R.
        Temporal and spatial relationships between lipopolysaccharide-induced expression of Fos, interleukin-1beta and inducible nitric oxide synthase in rat brain.
        Neuroscience. 1999; 89: 535-548
        • Laflamme N.
        • Lacroix S.
        • Rivest S.
        An essential role of interleukin-1β in mediating NF-kappa-B activity and COX-2 transcription in cells of the blood–brain barrier in response to a systemic and localized inflammation but not during endotoxemia.
        J. Neurosci. 1999; 19: 10923-10930
        • Laviano A.
        • Zhong-Jin Y.
        • Meguid M.M.
        • Koseki M.
        • Beverly J.L.
        Hepatic vagus does not mediate IL-1α induced anorexia.
        NeuroReport. 1995; 6: 1266-1268
        • Layé S.
        • Bluthé R.M.
        • Kent S.
        • Combe C.
        • Médina C.
        • Parnet P.
        • Kelley K.W.
        • Dantzer R.
        Subdiaphragmatic vagotomy blocks the induction of interleukin-1β mRNA in the brain of mice in response to peripherally administered lipopolysaccharide.
        Am. J. Physiol. 1995; 268: 1327-1331
        • Layé S.
        • Gheusi G.
        • Cremona S.
        • Combe C.
        • Kelley K.W.
        • Dantzer R.
        • Parnet P.
        Endogenous brain interleukin-1 mediates lipopolysaccharide-induced anorexia and brain cytokine expression.
        Am. J. Physiol. 2000; 279: R93-R98
        • Layé S.
        • Parnet P.
        • Goujon E.
        • Dantzer R.
        Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice.
        Mol. Brain Res. 1994; 27: 157-162
        • Li Y.W.
        • Ericsson A.
        • Sawchenko P.E.
        Distinct mechanisms underlie activation of hypothalamic neurosecretory neurons and their medullary catecholaminergic afferents in categorically different stress paradigms.
        Proc. Natl. Acad. Sci. USA. 1996; 93: 2359-2364
      2. Luheshi, G.N., Bluthé, R.M., Rusforth, D., Mulcahy, N., Konsman, J.P., Goldbach, M., Dantzer, R., 2000. Vagotomy attenuates the behavioural but not the pyrogenic effects of interleukin-1 in rats. Autonom. Neurosci. (this issue).

        • Plotkin S.R.
        • Banks W.A.
        • Kastin A.J.
        Comparison of saturable transport and extracellular pathways in the passage of interleukin-1 alpha across the blood–brain barrier.
        J. Neuroimmunol. 1996; 67: 41-47
        • Porter M.H.
        • Hrupka B.J.
        • Langhans W.
        • Schwartz G.J.
        Vagal and splanchnic afferents are not necessary for the anorexia produced by peripheral IL-1beta, LPS, and MDP.
        Am. J. Physiol. 1998; 275: R384-R389
        • Quan N.
        • Sundar S.K.
        • Weiss J.
        Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide.
        J. Neuroimmunol. 1994; 49: 125-134
        • Quan N.
        • Whiteside M.
        • Herkenham M.
        Time course and localisation patterns of interleukin-1 beta messenger RNA expression in brain and pituitary after peripheral administration of lipopolysaccharide.
        Neuroscience. 1998; 83: 281-293
        • Romanovsky A.A.
        • Simons C.T.
        • Szekely M.
        • Kulchitsky V.A.
        The vagus nerve in the thermoregulatory response to systemic inflammation.
        Am. J. Physiol. 1997; 273: R407-R413
        • Sagar S.M.
        • Price K.J.
        • Kasting N.W.
        • Sharp F.R.
        Anatomic patterns of Fos immunostaining in rat brain following systemic endotoxin administration.
        Brain Res. Bull. 1995; 36: 381-392
        • Saper C.B.
        • Breder C.D.
        Endogenous pyrogens in the CNS: role in the febrile response.
        Prog. Brain Res. 1992; 93: 419-428
        • Sawchenko P.E.
        • Brown E.R.
        • Chan R.K.
        • Ericsson A.
        • Li H.Y.
        • Roland B.L.
        • Kovacs K.J.
        The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress.
        Prog. Brain Res. 1996; 107: 201-222
        • Schwartz G.J.
        • Plata-Salaman C.R.
        • Langhans W.
        Subdiaphragmatic vagal deafferentation fails to block feeding-suppressive effects of LPS and IL-1β in rats.
        Am. J. Physiol. 1997; 273: R1193-R1198
        • Simons C.T.
        • Kulchitsky V.A.
        • Sugimoto N.
        • Homer L.D.
        • Szekely M.
        • Romanovsky A.A.
        Signalling the brain in systemic inflammation: which vagal branch is involved in fever genesis?.
        Am. J. Physiol. 1998; 275: R63-R68
        • Stitt J.T.
        Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats.
        J. Physiol. (Lond.). 1985; 368: 501-511
        • Stitt J.T.
        Prostaglandin E as the neural mediator of the febrile response.
        Yale J. Biol. Med. 1986; 59: 137-149
        • Tkacs N.C.
        • Li J.
        Immune stimulation induces Fos expression in brainstem amygdala afferents.
        Brain Res. Bull. 1999; 48: 223-231
        • Tkacs N.C.
        • Li J.
        • Strack A.M.
        Central amygdala Fos expression during hypotensive or febrile, non hypotensive endotoxemia in conscious rats.
        J. Comp. Neurol. 1997; 379: 592-602
        • Van Dam A.M.
        • Brouns M.
        • Louisse S.
        • Berkenbosch F.
        Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non specific symptoms of sickness?.
        Brain Res. 1992; 588: 291-296
        • Wan W.
        • Janz L.
        • Vriend C.Y.
        • Sorensen C.M.
        • Greenberg A.H.
        • Nance D.M.
        Differential induction of c-fos immunoreactivity in hypothalamus and brain stem nuclei following central and peripheral administration of endotoxin.
        Brain Res. Bull. 1993; 32: 581-587
        • Wan W.
        • Wetmore L.
        • Sorensen C.M.
        • Greenberg A.H.
        • Nance D.M.
        Neural and biochemical mediators of endotoxin- and stress-induced c-fos expression in the rat brain.
        Brain Res. Bull. 1994; 34: 7-14
        • Watkins L.R.
        • Goehler L.E.
        • Relton J.K.
        • Tartaglia N.
        • Silbert L.
        • Martin D.
        • Maier S.F.
        Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication.
        Neurosci. Lett. 1995; 183: 27-31
        • Watkins L.R.
        • Wiertelak E.P.
        • Goehler L.E.
        • Mooney-Heiberger K.
        • Martinez J.
        • Furness L.
        • Smith K.P.
        • Maier S.F.
        Neurocircuitry of illness-induced hyperalgesia.
        Brain Res. 1994; 639: 283-299
        • Williams C.L.
        • McGaugh J.L.
        Reversible lesions of the nucleus of the solitary tract attenuate the memory-modulating effects of posttraining epinephrine.
        Behav. Neurosci. 1993; 107: 955-962
        • Wong M.
        • Bongiorno P.B.
        • al-Sheklee A.
        • Esposito A.
        • Khatri P.
        • Licinio J.
        IL-1 beta, IL-1 receptor type I and iNOS gene expression in rat brain vasculature and perivascular areas.
        NeuroReport. 1996; 7: 2445-2448
        • Wong M.
        • Licinio J.
        Localisation of interleukin-1 type 1 receptor mRNA in rat brain.
        Neuroimmunomodulation. 1994; 1: 110-115
        • Yabuuchi K.
        • Minami M.
        • Katsumata S.
        • Satoh M.
        Localisation of type I interleukin-1 receptor mRNA in the rat brain.
        Mol. Brain Res. 1994; 27: 27-36