Skip to main content

Advertisement

SpringerLink
Log in

Immune-To-Brain Signaling: How Important are the Blood–Brain Barrier-independent Pathways?

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

A conceptual obstacle for understanding immune-to-brain signaling is the issue of the blood–brain barrier (BBB). In the last 30 years, several pathways have been investigated to address the question of how peripheral immune signals are transmitted into the brain. These pathways can be categorized into two types: BBB-dependent pathways and BBB-independent pathways. BBB-dependent pathways involve the BBB as a relay station or porous barrier, whereas BBB-independent pathways use neuronal routes that bypass the BBB. Recently, a complete BBB-dependent ascending pathway for immune-to-brain signaling has been described. Details of BBB-independent pathways are still under construction. In this review, I will summarize the current progress in unraveling immune-to-brain signaling pathways. In addition, I will provide a critical analysis of the literature to point to areas where our knowledge of the immunological afferent signaling to the central nervous system is still sorely lacking.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Plata-Salaman CR, Borkoski JP (1993) Centrally administered bacterial lipopolysaccharide depresses feeding in rats. Pharmacol Biochem Behav 46(4):787–791

    PubMed  CAS  Google Scholar 

  2. Foca A, Nicoletta P, Matera G, Mastroeni P, Caputi AP (1983) Antidipsogenic effect of endotoxin in the rat. Circ Shock 11(4):341–350

    PubMed  CAS  Google Scholar 

  3. Krueger JM, Majde JA (1995) Cytokines and sleep. Int Arch Allergy Immunol 106(2):97–100

    PubMed  CAS  Google Scholar 

  4. Eskay RL, Grino M, Chen HT (1990) Interleukins, signal transduction, and the immune system-mediated stress response. Adv Exp Med Biol 274:331–343

    PubMed  CAS  Google Scholar 

  5. Tracey KJ (2002) The inflammatory reflex. Nature 420(6917):853–859

    PubMed  CAS  Google Scholar 

  6. Kluger MJ, Ringler DH, Anver MR (1975) Fever and survival. Science 188(4184):166–168

    PubMed  CAS  Google Scholar 

  7. Bovbjerg D, Ader R, Cohen N (1982) Behaviorally conditioned suppression of a graft-versus-host response. Proc Natl Acad Sci USA 79(2):583–585

    PubMed  CAS  Google Scholar 

  8. Bovbjerg D, Cohen N, Ader R (1987) Behaviorally conditioned enhancement of delayed-type hypersensitivity in the mouse. Brain Behav Immun 1(1):64–71

    PubMed  CAS  Google Scholar 

  9. Alisjahbana B, Netea MG, van der Meer JW (2003) Pro-inflammatory cytokine response in acute infection. Adv Exp Med Biol 531:229–240

    PubMed  CAS  Google Scholar 

  10. Ching S, Zhang H, Belevych N et al (2007) Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration. J Neurosci 27(39):10476–10486

    PubMed  CAS  Google Scholar 

  11. Lesnikov VA, Efremov OM, Korneva EA, Van Damme J, Billiau A (1991) Fever produced by intrahypothalamic injection of interleukin-1 and interleukin-6. Cytokine 3(3):195–198

    PubMed  CAS  Google Scholar 

  12. Dinarello CA, Cannon JG, Mancilla J, Bishai I, Lees J, Coceani F (1991) Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells. Brain Res 562(2):199–206

    PubMed  CAS  Google Scholar 

  13. Sherman ML, Spriggs DR, Arthur KA, Imamura K, Frei E 3rd, Kufe DW (1988) Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism. J Clin Oncol 6(2):344–350

    PubMed  CAS  Google Scholar 

  14. Kakucska I, Qi Y, Clark BD, Lechan RM (1993) Endotoxin-induced corticotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus is mediated centrally by interleukin-1. Endocrinology 133(2):815–821

    PubMed  CAS  Google Scholar 

  15. Imeri L, Opp MR, Krueger JM (1993) An IL-1 receptor and an IL-1 receptor antagonist attenuate muramyl dipeptide- and IL-1-induced sleep and fever. Am J Physiol 265(4 Pt 2):R907–R913

    PubMed  CAS  Google Scholar 

  16. Lang CH, Cooney R, Vary TC (1996) Central interleukin-1 partially mediates endotoxin-induced changes in glucose metabolism. Am J Physiol 271(2 Pt 1):E309–E316

    PubMed  CAS  Google Scholar 

  17. Blatteis CM, Bealer SL, Hunter WS, Llanos QJ, Ahokas RA, Mashburn TA Jr (1983) Suppression of fever after lesions of the anteroventral third ventricle in guinea pigs. Brain Res Bull 11(5):519–526

    PubMed  CAS  Google Scholar 

  18. Elmquist JK, Scammell TE, Jacobson CD, Saper CB (1996) Distribution of Fos-like immunoreactivity in the rat brain following intravenous lipopolysaccharide administration. J Comp Neurol 371(1):85–103

    PubMed  CAS  Google Scholar 

  19. Stitt JT (1985) Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats. J Physiol 368:501–511

    PubMed  CAS  Google Scholar 

  20. Takahashi Y, Smith P, Ferguson A, Pittman QJ (1997) Circumventricular organs and fever. Am J Physiol 273(5 Pt 2):R1690–R1695

    PubMed  CAS  Google Scholar 

  21. Lee HY, Whiteside MB, Herkenham M (1998) Area postrema removal abolishes stimulatory effects of intravenous interleukin-1beta on hypothalamic-pituitary-adrenal axis activity and c- fos mRNA in the hypothalamic paraventricular nucleus. Brain Res Bull 46(6):495–503

    PubMed  CAS  Google Scholar 

  22. Ericsson A, Arias C, Sawchenko PE (1997) Evidence for an intramedullary prostaglandin-dependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1. J Neurosci 17(18):7166–7179

    PubMed  CAS  Google Scholar 

  23. Romanovsky AA, Sugimoto N, Simons CT, Hunter WS (2003) The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments. Am J Physiol Regul Integr Comp Physiol 285(2):R420–R428

    PubMed  CAS  Google Scholar 

  24. Peruzzo B, Pastor FE, Blazquez JL et al (2000) A second look at the barriers of the medial basal hypothalamus. Exp Brain Res 132(1):10–26

    PubMed  CAS  Google Scholar 

  25. Breder CD, Hazuka C, Ghayur T et al (1994) Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration. Proc Natl Acad Sci USA 91(24):11393–11397

    PubMed  CAS  Google Scholar 

  26. Nakamori T, Morimoto A, Yamaguchi K, Watanabe T, Long NC, Murakami N (1993) Organum vasculosum laminae terminalis (OVLT) is a brain site to produce interleukin-1 beta during fever. Brain Res 618(1):155–159

    PubMed  CAS  Google Scholar 

  27. Vallieres L, Rivest S (1997) Regulation of the genes encoding interleukin-6, its receptor, and gp130 in the rat brain in response to the immune activator lipopolysaccharide and the proinflammatory cytokine interleukin-1beta. J Neurochem 69(4):1668–1683

    Article  PubMed  CAS  Google Scholar 

  28. Nadeau S, Rivest S (1999) Regulation of the gene encoding tumor necrosis factor alpha (TNF-alpha) in the rat brain and pituitary in response in different models of systemic immune challenge. J Neuropathol Exp Neurol 58(1):61–77

    PubMed  CAS  Google Scholar 

  29. Quan N, Whiteside M, Herkenham M (1998) Time course and localization patterns of interleukin-1b messenger RNA expression in brain and pituitary after peripheral administration of lipopolysaccharide. Neuroscience 83:281–293

    PubMed  CAS  Google Scholar 

  30. Ericsson A, Liu C, Hart RP, Sawchenko PE (1995) Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1-induced cellular activation. J Comp Neurol 361(4):681–698

    PubMed  CAS  Google Scholar 

  31. Laflamme N, Rivest S (2001) Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating Gram-negative bacterial cell wall components. FASEB J 15(1):155–163

    PubMed  CAS  Google Scholar 

  32. Rivest S (2003) Molecular insights on the cerebral innate immune system. Brain Behav Immun 17(1):13–19

    PubMed  CAS  Google Scholar 

  33. Lacroix S, Feinstein D, Rivest S (1998) The bacterial endotoxin lipopolysaccharide has the ability to target the brain in upregulating its membrane CD14 receptor within specific cellular populations. Brain Pathol 8(4):625–640

    PubMed  CAS  Google Scholar 

  34. Quan N, Whiteside M, Kim L, Herkenham M (1997) Induction of inhibitory factor kBa mRNA in the central nervous system after peripheral lipopolysaccharide administration: an in situ hybridization histochemistry study in the rat. Proc Natl Acad Sci USA 94:10985–10990

    PubMed  CAS  Google Scholar 

  35. Harre EM, Roth J, Gerstberger R, Hubschle T (2003) Interleukin-6 mediates lipopolysaccharide-induced nuclear STAT3 translocation in astrocytes of rat sensory circumventricular organs. Brain Res 980(1):151–155

    PubMed  CAS  Google Scholar 

  36. McKinley MJ, Hards DK, Oldfield BJ (1994) Identification of neural pathways activated in dehydrated rats by means of Fos-immunohistochemistry and neural tracing. Brain Res 653(1–2):305–314

    PubMed  CAS  Google Scholar 

  37. Larsen PJ, Mikkelsen JD (1995) Functional identification of central afferent projections conveying information of acute “stress” to the hypothalamic paraventricular nucleus. J Neurosci 15(4):2609–2627

    PubMed  CAS  Google Scholar 

  38. Silverman AJ, Hoffman DL, Zimmerman EA (1981) The descending afferent connections of the paraventricular nucleus of the hypothalamus (PVN). Brain Res Bull 6(1):47–61

    PubMed  CAS  Google Scholar 

  39. Ciriello J, Gutman MB (1991) Functional identification of central pressor pathways originating in the subfornical organ. Can J Physiol Pharmacol 69(7):1035–1045

    PubMed  CAS  Google Scholar 

  40. Cottrell GT, Ferguson AV (2004) Sensory circumventricular organs: central roles in integrated autonomic regulation. Regul Pept 117(1):11–23

    PubMed  CAS  Google Scholar 

  41. Banks WA, Kastin AJ, Broadwell RD (1995) Passage of cytokines across the blood–brain barrier. Neuroimmunomodulation 2:241–248

    PubMed  CAS  Google Scholar 

  42. Banks WA, Kastin AJ (1997) Relative contributions of peripheral and central sources to levels of IL-1 alpha in the cerebral cortex of mice: assessment with species- specific enzyme immunoassays. J Neuroimmunol 79(1):22–28

    PubMed  CAS  Google Scholar 

  43. Pan W, Kastin AJ (2002) TNFa transport across the blood–brain barrier is abolished in receptor knockout mice. Exp Neurol 174:193–200

    PubMed  CAS  Google Scholar 

  44. Banks WA, Farr SA, La Scola ME, Morley JE (2001) Intravenous human interleukin-1alpha impairs memory processing in mice: dependence on blood–brain barrier transport into posterior division of the septum. J Pharmacol Exp Ther 299(2):536–541

    PubMed  CAS  Google Scholar 

  45. Quan N, Banks WA (2007) Brain-immune communication pathways. Brain Behav Immun 21(6):727–735

    PubMed  CAS  Google Scholar 

  46. Cunningham ETJ, Wada E, Carter DB, Tracey DE, Battey JF, De Souza EB (1992) In situ histochemical localization of type I interleukin-1 receptor messenger RNA in the central nervous system, pituitary, and adrenal gland of the mouse. J Neurosci 12(3):1101–1114

    PubMed  CAS  Google Scholar 

  47. Van Dam AM, De Vries HE, Kuiper J et al (1996) Interleukin-1 receptors on rat brain endothelial cells: a role in neuroimmune interaction? FASEB J 10(2):351–356

    PubMed  Google Scholar 

  48. Konsman JP, Vigues S, Mackerlova L, Bristow A, Blomqvist A (2004) Rat brain vascular distribution of interleukin-1 type-1 receptor immunoreactivity: relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli. J Comp Neurol 472(1):113–129

    PubMed  Google Scholar 

  49. Bebo BF Jr, Linthicum DS (1995) Expression of mRNA for 55-kDa and 75-kDa tumor necrosis factor (TNF) receptors in mouse cerebrovascular endothelium: effects of interleukin-1 beta, interferon-gamma and TNF-alpha on cultured cells. J Neuroimmunol 62(2):161–167

    PubMed  CAS  Google Scholar 

  50. Vallieres L, Rivest S (1999) Interleukin-6 is a needed proinflammatory cytokine in the prolonged neural activity and transcriptional activation of corticotropin-releasing factor during endotoxemia. Endocrinology 140(9):3890–3903

    PubMed  CAS  Google Scholar 

  51. Rummel C, Voss T, Matsumura K et al (2005) Nuclear STAT3 translocation in guinea pig and rat brain endothelium during systemic challenge with lipopolysaccharide and interleukin-6. J Comp Neurol 491(1):1–14

    PubMed  CAS  Google Scholar 

  52. Quan N, He L, Lai W (2003) Endothelial activation is an intermediate step for peripheral lipopolysaccharide induced activation of paraventricular nucleus. Brain Res Bull 59(6):447–452

    PubMed  CAS  Google Scholar 

  53. Sanchez-Alavez M, Tabarean IV, Behrens MM, Bartfai T (2006) Ceramide mediates the rapid phase of febrile response to IL-1beta. Proc Natl Acad Sci USA 103(8):2904–2908

    PubMed  CAS  Google Scholar 

  54. Quan N, Whiteside M, Herkenham M (1998) Cyclooxygenase 2 mRNA expression in rat brain after peripheral injection of lipopolysaccharide. Brain Res 802(1–2):189–197

    PubMed  CAS  Google Scholar 

  55. Cao C, Matsumura K, Yamagata K, Watanabe Y (1997) Involvement of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA by LPS in the rat brain. Am J Physiol 272(6 Pt 2):R1712–R1725

    PubMed  CAS  Google Scholar 

  56. Engblom D, Saha S, Engstrom L et al (2003) Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nat Neurosci 6(11):1137–1138

    PubMed  CAS  Google Scholar 

  57. Ek M, Engblom D, Saha S, Blomqvist A, Jakobsson PJ, Ericsson-Dahlstrand A (2001) Inflammatory response: pathway across the blood–brain barrier. Nature 410(6827):430–431

    PubMed  CAS  Google Scholar 

  58. Yamagata K, Matsumura K, Inoue W et al (2001) Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever. J Neurosci 21(8):2669–2677

    PubMed  CAS  Google Scholar 

  59. Lazarus M, Yoshida K, Coppari R et al (2007) EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Nat Neurosci 10(9):1131–1133

    PubMed  CAS  Google Scholar 

  60. Gosselin D, Rivest S (2008) MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation. Mol Psychiatry 13:480–497

    PubMed  CAS  Google Scholar 

  61. Steiner AA, Chakravarty S, Rudaya AY, Herkenham M, Romanovsky AA (2006) Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells. Blood 107(10):4000–4002

    PubMed  CAS  Google Scholar 

  62. Schiltz JC, Sawchenko PE (2002) Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. J Neurosci 22(13):5606–5618

    PubMed  CAS  Google Scholar 

  63. Wiik H, Karttunen R, Haukipuro K, Syrjala H (2001) Maximal local and minimal systemic cytokine response to colorectal surgery: the influence of perioperative filgrastim. Cytokine 14(3):188–192

    PubMed  CAS  Google Scholar 

  64. Yamamoto T, Umegae S, Kitagawa T, Matsumoto K (2005) Systemic and local cytokine production in quiescent ulcerative colitis and its relationship to future relapse: a prospective pilot study. Inflamm Bowel Dis 11(6):589–596

    PubMed  Google Scholar 

  65. Hedges SR, Barrientes F, Desmond RA, Schwebke JR (2006) Local and systemic cytokine levels in relation to changes in vaginal flora. J Infect Dis 193(4):556–562

    PubMed  CAS  Google Scholar 

  66. Cavaillon JM, Annane D (2006) Compartmentalization of the inflammatory response in sepsis and SIRS. J Endotoxin Res 12(3):151–170

    PubMed  CAS  Google Scholar 

  67. Makhija R, Kingsnorth AN (2002) Cytokine storm in acute pancreatitis. J Hepatobiliary Pancreat Surg 9(4):401–410

    PubMed  Google Scholar 

  68. O’Nuallain EM, Puri P, Mealy K, Reen DJ (1995) Induction of interleukin-1 receptor antagonist (IL-1ra) following surgery is associated with major trauma. Clin Immunol Immunopathol 76(1 Pt 1):96–101

    PubMed  CAS  Google Scholar 

  69. Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C, Payen D (2003) Cytokine cascade in sepsis. Scand J Infect Dis 35(9):535–544

    PubMed  CAS  Google Scholar 

  70. Munford RS, Pugin J (2001) Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 163(2):316–321

    PubMed  CAS  Google Scholar 

  71. Creasey AA, Stevens P, Kenney J et al (1991) Endotoxin and cytokine profile in plasma of baboons challenged with lethal and sublethal Escherichia coli. Circ Shock 33(2):84–91

    PubMed  CAS  Google Scholar 

  72. Anthony DC, Bolton SJ, Fearn S, Perry VH (1997) Age-related effects of interleukin-1 beta on polymorphonuclear neutrophil-dependent increases in blood–brain barrier permeability in rats. Brain 120(Pt 3):435–444

    PubMed  Google Scholar 

  73. Ching S, He L, Lai W, Quan N (2005) IL-1 type I receptor plays a key role in mediating the recruitment of leukocytes into the central nervous system. Brain Behav Immun 19(2):127–137

    PubMed  CAS  Google Scholar 

  74. Nadeau S, Rivest S (2002) Endotoxemia prevents the cerebral inflammatory wave induced by intraparenchymal lipopolysaccharide injection: role of glucocorticoids and CD14. J Immunol 169(6):3370–3381

    PubMed  CAS  Google Scholar 

  75. Ching S, Zhang H, Lai W, Quan N (2006) Peripheral injection of lipopolysaccharide prevents brain recruitment of leukocytes induced by central injection of interleukin-1. Neuroscience 137(2):717–726

    PubMed  CAS  Google Scholar 

  76. McColl BW, Rothwell NJ, Allan SM (2007) Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms. J Neurosci 27(16):4403–4412

    PubMed  CAS  Google Scholar 

  77. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25(40):9275–9284

    PubMed  CAS  Google Scholar 

  78. Romanovsky AA (2004) Signaling the brain in the early sickness syndrome: are sensory nerves involved? Front Biosci 9:494–504

    PubMed  CAS  Google Scholar 

  79. Bluthe RM, Walter V, Parnet P et al (1994) Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism. C R Acad Sci Ser III 317(6):499–503

    PubMed  CAS  Google Scholar 

  80. Watkins LR, Wiertelak EP, Goehler LE, Smith KP, Martin D, Maier SF (1994) Characterization of cytokine-induced hyperalgesia. Brain Res 654(1):15–26

    PubMed  CAS  Google Scholar 

  81. Maier SF, Goehler LE, Fleshner M, Watkins LR (1998) The role of the vagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci 840:289–300

    PubMed  CAS  Google Scholar 

  82. Sehic E, Blatteis CM (1996) Blockade of lipopolysaccharide-induced fever by subdiaphragmatic vagotomy in guinea pigs. Brain Res 726(1–2):160–166

    PubMed  CAS  Google Scholar 

  83. Watkins LR, Goehler LE, Relton JK et al (1995) Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci Lett 183(1–2):27–31

    PubMed  CAS  Google Scholar 

  84. Hansen MK, O’Connor KA, Goehler LE, Watkins LR, Maier SF (2001) The contribution of the vagus nerve in interleukin-1beta-induced fever is dependent on dose. Am J Physiol Regul Integr Comp Physiol 280(4):R929–R934

    PubMed  CAS  Google Scholar 

  85. Romanovsky AA, Simons CT, Szekely M, Kulchitsky VA (1997) The vagus nerve in the thermoregulatory response to systemic inflammation. Am J Physiol 273(1 Pt 2):R407–R413

    PubMed  CAS  Google Scholar 

  86. Luheshi GN, Bluthe RM, Rushforth D et al (2000) Vagotomy attenuates the behavioural but not the pyrogenic effects of interleukin-1 in rats. Auton Neurosci 85(1–3):127–132

    PubMed  CAS  Google Scholar 

  87. Bret-Dibat JL, Bluthe RM, Kent S, Kelley KW, Dantzer R (1995) Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism. Brain Behav Immun 9(3):242–246

    PubMed  CAS  Google Scholar 

  88. Porter MH, Hrupka BJ, Langhans W, Schwartz GJ (1998) Vagal and splanchnic afferents are not necessary for the anorexia produced by peripheral IL-1beta, LPS, and MDP. Am J Physiol 275(2 Pt 2):R384–R389

    PubMed  CAS  Google Scholar 

  89. Wieczorek M, Swiergiel AH, Pournajafi-Nazarloo H, Dunn AJ (2005) Physiological and behavioral responses to interleukin-1beta and LPS in vagotomized mice. Physiol Behav 85(4):500–511

    PubMed  CAS  Google Scholar 

  90. Fleshner M, Goehler LE, Hermann J, Relton JK, Maier SF, Watkins LR (1995) Interleukin-1 beta induced corticosterone elevation and hypothalamic NE depletion is vagally mediated. Brain Res Bull 37(6):605–610

    PubMed  CAS  Google Scholar 

  91. MohanKumar SM, MohanKumar PS, Quadri SK (2000) Effects of bacterial lipopolysaccharide on central monoamines and fever in the rat: involvement of the vagus. Neurosci Lett 284(3):159–162

    PubMed  CAS  Google Scholar 

  92. Wieczorek M, Dunn AJ (2006) Effect of subdiaphragmatic vagotomy on the noradrenergic and HPA axis activation induced by intraperitoneal interleukin-1 administration in rats. Brain Res 1101(1):73–84

    PubMed  CAS  Google Scholar 

  93. Ootsuka Y, Blessing WW, Steiner AA, Romanovsky AA (2008) Fever response to intravenous prostaglandin E2 is mediated by the brain but does not require afferent vagal signaling. Am J Physiol Regul Integr Comp Physiol 294(4):R1294–R1303

    PubMed  CAS  Google Scholar 

  94. Laye S, Bluthe RM, Kent S et al (1995) Subdiaphragmatic vagotomy blocks induction of IL-1 beta mRNA in mice brain in response to peripheral LPS. Am J Physiol 268(5 Pt 2):R1327–R1331

    PubMed  CAS  Google Scholar 

  95. Hansen MK, Taishi P, Chen Z, Krueger JM (1998) Vagotomy blocks the induction of interleukin-1beta (IL-1beta) mRNA in the brain of rats in response to systemic IL-1beta. J Neurosci 18(6):2247–2253

    PubMed  CAS  Google Scholar 

  96. Hansen MK, Nguyen KT, Goehler LE et al (2000) Effects of vagotomy on lipopolysaccharide-induced brain interleukin-1beta protein in rats. Auton Neurosci 85(1–3):119–126

    PubMed  CAS  Google Scholar 

  97. van Dam A-M, Brouns M, Louisse S, Berkenbosch F (1992) 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 588:291–296

    PubMed  Google Scholar 

  98. Proescholdt MG, Chakravarty S, Foster JA, Foti SB, Briley EM, Herkenham M (2002) Intracerebroventricular but not intravenous interleukin-1beta induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neuroscience 112(3):731–749

    PubMed  CAS  Google Scholar 

  99. Goehler LE, Gaykema RP, Opitz N, Reddaway R, Badr N, Lyte M (2005) Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun 19(4):334–344

    PubMed  Google Scholar 

  100. Campisi J, Hansen MK, O’Connor KA et al (2003) Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E. coli challenge. J Appl Physiol 95(5):1873–1882

    PubMed  CAS  Google Scholar 

  101. Blatteis CM (2007) The onset of fever: new insights into its mechanism. Prog Brain Res 162:3–14

    Article  PubMed  CAS  Google Scholar 

  102. Blatteis CM, Li S, Li Z, Perlik V, Feleder C (2004) Signaling the brain in systemic inflammation: the role of complement. Front Biosci 9:915–931

    PubMed  CAS  Google Scholar 

  103. Blatteis CM (2006) Endotoxic fever: new concepts of its regulation suggest new approaches to its management. Pharmacol Ther 111(1):194–223

    PubMed  CAS  Google Scholar 

  104. Simons CT, Kulchitsky VA, Sugimoto N, Homer LD, Szekely M, Romanovsky AA (1998) Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis? Am J Physiol 275(1 Pt 2):R63–R68

    PubMed  CAS  Google Scholar 

  105. Steiner AA, Ivanov AI, Serrats J et al (2006) Cellular and molecular bases of the initiation of fever. PLoS Biol 4(9):e284

    PubMed  Google Scholar 

  106. Cartmell T, Poole S, Turnbull AV, Rothwell NJ, Luheshi GN (2000) Circulating interleukin-6 mediates the febrile response to localised inflammation in rats. J Physiol 526(Pt 3):653–661

    PubMed  CAS  Google Scholar 

  107. Miller AJ, Hopkins SJ, Luheshi GN (1997) Sites of action of IL-1 in the development of fever and cytokine responses to tissue inflammation in the rat. Br J Pharmacol 120(7):1274–1279

    PubMed  CAS  Google Scholar 

  108. Kozak W, Kluger MJ, Soszynski D et al (1998) IL-6 and IL-1 beta in fever. Studies using cytokine-deficient (knockout) mice. Ann NY Acad Sci 856:33–47

    PubMed  CAS  Google Scholar 

  109. Roth J, De Souza GE (2001) Fever induction pathways: evidence from responses to systemic or local cytokine formation. Braz J Med Biol Res 34(3):301–314

    PubMed  CAS  Google Scholar 

  110. Rummel C, Barth SW, Voss T et al (2005) Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways? Am J Physiol Regul Integr Comp Physiol 289(2):R340–R347

    PubMed  CAS  Google Scholar 

  111. Cooper AL, Rothwell NJ (1991) Mechanisms of early and late hypermetabolism and fever after localized tissue injury in rats. Am J Physiol 261(6 Pt 1):E698–E705

    PubMed  CAS  Google Scholar 

  112. Goldbach JM, Roth J, Zeisberger E (1997) Fever suppression by subdiaphragmatic vagotomy in guinea pigs depends on the route of pyrogen administration. Am J Physiol 272(2 Pt 2):R675–R681

    PubMed  CAS  Google Scholar 

  113. Borovikova LV, Ivanova S, Zhang M et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405(6785):458–462

    PubMed  CAS  Google Scholar 

  114. Lussier A, de Medicis R, Tetreault L (1981) Adjuvant arthritis: influence of the adjuvant volume and composition on the non-specific inflammation. Int J Tissue React 3(1):11–15

    PubMed  CAS  Google Scholar 

  115. Connolly KM, Stecher VJ, Danis E, Pruden DJ, LaBrie T (1988) Alteration of interleukin-1 production and the acute phase response following medication of adjuvant arthritic rats with cyclosporin-A or methotrexate. Int J Immunopharmacol 10(6):717–728

    PubMed  CAS  Google Scholar 

  116. Eski M, Sahin I, Sengezer M, Serdar M, Ifran A (2008) Thalidomide decreases the plasma levels of IL-1 and TNF following burn injury: is it a new drug for modulation of systemic inflammatory response. Burns 34(1):104–108

    PubMed  Google Scholar 

  117. Engblom D, Ek M, Andersson IM et al (2002) Induction of microsomal prostaglandin E synthase in the rat brain endothelium and parenchyma in adjuvant-induced arthritis. J Comp Neurol 452(3):205–214

    PubMed  CAS  Google Scholar 

  118. Ozaki-Okayama Y, Matsumura K, Ibuki T et al (2004) Burn injury enhances brain prostaglandin E2 production through induction of cyclooxygenase-2 and microsomal prostaglandin E synthase in cerebral vascular endothelial cells in rats. Crit Care Med 32(3):795–800

    PubMed  Google Scholar 

  119. Saha S, Engstrom L, Mackerlova L, Jakobsson PJ, Blomqvist A (2005) Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-1. Am J Physiol Regul Integr Comp Physiol 288(5):R1100–R1107

    PubMed  CAS  Google Scholar 

  120. Oka Y, Ibuki T, Matsumura K et al (2007) Interleukin-6 is a candidate molecule that transmits inflammatory information to the CNS. Neuroscience 145(2):530–538

    PubMed  CAS  Google Scholar 

  121. Guay J, Bateman K, Gordon R, Mancini J, Riendeau D (2004) Carrageenan-induced paw edema in rat elicits a predominant prostaglandin E2 (PGE2) response in the central nervous system associated with the induction of microsomal PGE2 synthase-1. J Biol Chem 279(23):24866–24872

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study is supported by R01 AI059089 and R01 AI076926. I would like to thank Dr. Miles Herkenham for his careful reading of the manuscript and many valuable suggestions. I would also like to thank Dr. Qun Chen for his help in making the illustration in this paper.

Author information

Authors and Affiliations

  1. Institute of Behavior Medicine, Ohio State University, 4179 Postle Hall, 305 W. 12th Ave, Columbus, OH, 43210-1094, USA

    Ning Quan

Authors
  1. Ning Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ning Quan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Quan, N. Immune-To-Brain Signaling: How Important are the Blood–Brain Barrier-independent Pathways?. Mol Neurobiol 37, 142–152 (2008). https://doi.org/10.1007/s12035-008-8026-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-008-8026-z

Keywords

Search

Navigation