MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation

Activation of neuronal circuits involved in the control of autonomic responses is critical for the host survival to immune threats. The brain vascular system plays a key role in such immune-CNS communication, but the signaling pathway and exact type of cells within the blood-brain barrier (BBB) mediating these functions have yet to be uncovered. To elucidate this issue we used myeloid differentiation factor 88 (MyD88)-deficient mice, because these animals do not show any responses to the cytokine interleukin-1β (IL-1β). We created chimeric mice with competent MyD88 signaling in either the BBB endothelium or perivascular microglia of bone marrow origin and challenged them with IL-1β. Systemic treatment with the cytokine caused a robust transcriptional activation of genes involved in the prostaglandin E2 (PGE2) production by vascular cells of the brain. Upregulation of these genes is dependent on a functional MyD88 signaling in the endothelium, because MyD88-deficient mice that received bone marrow stem cells from wild-type animals (for example, functional perivascular microglia) exhibited no response to systemic IL-1β administration. MyD88 competent endothelial cells also mediate neuronal activation and plasma release of glucocorticoids, whereas chimeric mice with MyD88-competent perivascular microglia did not show a significant increase of these functions. Moreover, competent endothelial cells for the gene encoding Toll-like receptor 4 (TLR4) are essential for the release of plasma corticosterone in response to low and high doses of lipopolysaccharide. Therefore, BBB endothelial cells and not perivascular microglia are the main target of circulating inflammatory mediators to activate the brain circuits and key autonomic functions during systemic immune challenges.

[1]  S. Rivest.  How circulating cytokines trigger the neural circuits that control the hypothalamic–pituitary–adrenal axis , 2001, Psychoneuroendocrinology.

[2]  E. Sternberg,et al.  Neuroendocrine regulation of immunity. , 2003, Annual review of immunology.

[3]  S. Rivest,et al.  Unraveling the Molecular Details Involved in the Intimate Link between the Immune and Neuroendocrine Systems , 2004, Experimental biology and medicine.

[4]  A. Arimura,et al.  Adrenocorticotropin release induced by intracerebroventricular injection of recombinant human interleukin-1 in rats: possible involvement of prostaglandin. , 1988, Endocrinology.

[5]  Y. Watanabe,et al.  Electron Microscopic Evidence for Induction of Cyclooxygenase‐2 in Brain Endothelial Cells , 1998, Annals of the New York Academy of Sciences.

[6]  K. Nakadate,et al.  Brain Endothelial Cells Express Cyclooxygenase-2 during Lipopolysaccharide-Induced Fever: Light and Electron Microscopic Immunocytochemical Studies , 1998, The Journal of Neuroscience.

[7]  S. Rivest,et al.  Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  S. Rivest,et al.  An Essential Role of Interleukin-1β in Mediating NF-κB Activity and COX-2 Transcription in Cells of the Blood–Brain Barrier in Response to a Systemic and Localized Inflammation But Not During Endotoxemia , 1999, The Journal of Neuroscience.

[9]  Y. Wang,et al.  The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2−/−, but not in cyclooxygenase-1−/− mice , 1999, Brain Research.

[10]  R. Landmann,et al.  Cooperation between toll‐like receptor 2 and 4 in the brain of mice challenged with cell wall components derived from gram‐negative and gram‐positive bacteria , 2003, European journal of immunology.

[11]  S. Rivest,et al.  Functional circuitry in the brain of immune‐challenged rats: Partial involvement of prostaglandins , 1997, The Journal of comparative neurology.

[12]  M. Runge,et al.  Hypoxia Induces Cyclooxygenase-2 via the NF-κB p65 Transcription Factor in Human Vascular Endothelial Cells* , 1997, The Journal of Biological Chemistry.

[13]  K. Yamagata,et al.  Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor. , 1998, Brain research. Molecular brain research.

[14]  S. Akira,et al.  Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. , 1998, Immunity.

[15]  P. Sawchenko,et al.  Bone Marrow-Derived Cells that Populate the Adult Mouse Brain Preserve Their Hematopoietic Identity , 2003, The Journal of Neuroscience.

[16]  K. Yamagata,et al.  Coexpression of Microsomal-Type Prostaglandin E Synthase with Cyclooxygenase-2 in Brain Endothelial Cells of Rats during Endotoxin-Induced Fever , 2001, The Journal of Neuroscience.

[17]  A. A. Romanovsky,et al.  Expanding the febrigenic role of cyclooxygenase-2 to the previously overlooked responses. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[18]  B. Rabin,et al.  Central administration of prostaglandin E2 suppresses in vitro cellular immune responses. , 1995, The American journal of physiology.

[19]  S. Rivest,et al.  A Functional Analysis of EP4 Receptor‐Expressing Neurons in Mediating the Action of Prostaglandin E2 Within Specific Nuclei of the Brain in Response to Circulating Interleukin‐1β , 2000, Journal of neurochemistry.

[20]  S. Rivest.  What is the cellular source of prostaglandins in the brain in response to systemic inflammation? Facts and controversies , 1999, Molecular Psychiatry.

[21]  A. Blomqvist,et al.  Inflammatory response: Pathway across the blood–brain barrier , 2001, Nature.

[22]  C. Saper,et al.  Ventromedial Preoptic Prostaglandin E2 Activates Fever-Producing Autonomic Pathways , 1996, The Journal of Neuroscience.

[23]  K. Matsumura,et al.  Lipopolysaccharide Injected into the Cerebral Ventricle Evokes Fever through Induction of Cyclooxygenase-2 in Brain Endothelial Cells , 1999, The Journal of Neuroscience.

[24]  P. Sawchenko,et al.  Signaling the brain in systemic inflammation: the role of perivascular cells. , 2003, Frontiers in bioscience : a journal and virtual library.

[25]  S. Rivest,et al.  Effects of Systemic Immunogenic Insults and Circulating Proinflammatory Cytokines on the Transcription of the Inhibitory Factor κBα Within Specific Cellular Populations of the Rat Brain , 1999, Journal of neurochemistry.

[26]  M. Zaretskaia,et al.  Microinjection of prostaglandin E2 and muscimol into the preoptic area in conscious rats: Comparison of effects on plasma adrenocorticotrophic hormone (ACTH), body temperature, locomotor activity, and cardiovascular function , 2006, Neuroscience Letters.

[27]  S. Rivest,et al.  Cyclooxygenase 2 (COX‐2) inhibition increases the inflammatory response in the brain during systemic immune stimuli , 2005, Journal of neurochemistry.

[28]  T. Watanabe,et al.  ACTH response induced by interleukin-1 is mediated by CRF secretion stimulated by hypothalamic PGE , 1990, Experientia.

[29]  S. Rivest,et al.  In altering the release of glucocorticoids, ketorolac exacerbates the effects of systemic immune stimuli on expression of proinflammatory genes in the brain. , 2002, Endocrinology.

[30]  N. Quan,et al.  Intraventricular infusion of antagonists of IL-1 and TNFα attenuates neurodegeneration induced by the infection of Trypanosoma brucei , 2003, Journal of Neuroimmunology.

[31]  P. Sawchenko,et al.  Evidence for an Intramedullary Prostaglandin-Dependent Mechanism in the Activation of Stress-Related Neuroendocrine Circuitry by Intravenous Interleukin-1 , 1997, The Journal of Neuroscience.

[32]  T. Tanabe,et al.  Transcriptional role of the nuclear factor kappa B site in the induction by lipopolysaccharide and suppression by dexamethasone of cyclooxygenase-2 in U937 cells. , 1998, Biochemical and biophysical research communications.

[33]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[34]  B. Wisse,et al.  MyD88 is a key mediator of anorexia, but not weight loss, induced by lipopolysaccharide and interleukin-1 beta. , 2006, Endocrinology.

[35]  K. Yamagata,et al.  Involvement of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA by LPS in the rat brain. , 1997, The American journal of physiology.

[36]  Sumana Chakravarty,et al.  Toll-Like Receptor 4 on Nonhematopoietic Cells Sustains CNS Inflammation during Endotoxemia, Independent of Systemic Cytokines , 2005, The Journal of Neuroscience.

[37]  S. Akira,et al.  Toll-like receptors. , 2003, Annual review of immunology.

[38]  S. Rivest,et al.  Is survival possible without arachidonate metabolites in the brain during systemic infection? , 2003, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[39]  W. Zhang,et al.  Protein-protein interactions involving inducible nitric oxide synthase. , 2003, Acta physiologica Scandinavica.

[40]  L. Ballou,et al.  Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1β , 2001, Brain Research.

[41]  M. Herkenham,et al.  Cyclooxygenase 2 mRNA expression in rat brain after peripheral injection of lipopolysaccharide , 1998, Brain Research.

[42]  C. J. McCarthy,et al.  Involvement of nuclear factor kappa B in the regulation of cyclooxygenase-2 expression by interleukin-1 in rheumatoid synoviocytes. , 1997, Arthritis and rheumatism.

[43]  Yasuyoshi Watanabe,et al.  Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1β: a possible site of prostaglandin synthesis responsible for fever , 1996, Brain Research.

[44]  S. Rivest,et al.  Inhibitory Action of Nitric Oxide on Circulating Tumor Necrosis Factor‐Induced NF‐κB Activity and COX‐2 Transcription in the Endothelium of the Brain Capillaries , 2001, Journal of neuropathology and experimental neurology.

[45]  Y. Watanabe,et al.  Induction of Cyclooxygenase‐2 in the Brain by Cytokines , 1997, Annals of the New York Academy of Sciences.

[46]  S. Rivest.  Activation of the nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2) genes in cerebral blood vessels in response to systemic inflammation , 1999, Molecular Psychiatry.

[47]  S. Rivest,et al.  Irradiation Does Not Compromise or Exacerbate the Innate Immune Response in the Brains of Mice That Were Transplanted with Bone Marrow Stem Cells , 2007, Stem cells.

[48]  Anders Blomqvist,et al.  Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis , 2003, Nature Neuroscience.

[49]  Makoto Murakami,et al.  Recent advances in molecular biology and physiology of the prostaglandin E2-biosynthetic pathway. , 2004, Progress in lipid research.

[50]  C. Saper,et al.  Intravenous lipopolysaccharide induces cyclooxygenase 2‐like immunoreactivity in rat brain perivascular microglia and meningeal macrophages , 1997, The Journal of comparative neurology.

[51]  P. Sawchenko,et al.  Distinct Brain Vascular Cell Types Manifest Inducible Cyclooxygenase Expression as a Function of the Strength and Nature of Immune Insults , 2002, The Journal of Neuroscience.

[52]  R. Robertson,et al.  Basal expression of cyclooxygenase-2 and nuclear factor-interleukin 6 are dominant and coordinately regulated by interleukin 1 in the pancreatic islet. , 1998, Proceedings of the National Academy of Sciences of the United States of America.