The circumventricular organs participate in the immunopathogenesis of experimental autoimmune encephalomyelitis
Tóm tắt
During inflammatory conditions of the central nervous system (CNS), such as in multiple sclerosis or in its animal model, experimental autoimmune encephalomyelitis (EAE), immune cells migrate from the blood stream into the CNS parenchyma and into the cerebrospinal fluid (CSF) spaces. The endothelial blood-brain barrier (BBB) has been considered the most obvious entry site for circulating immune cells. Recently, the choroid plexus has been considered as an alternative entry site for circulating lymphocytes into the CSF. The choroid plexus, belongs to the circumventricular organs (CVOs) localized in the walls of the ventricles. Other CVOs, which similar to the choroid plexus lack an endothelial BBB, have not been considered as possible entry sites for immune cells into the CNS parenchyma or the CSF. Here we asked, whether CVOs are involved in the recruitment of inflammatory cells into the brain during EAE. We performed an extensive immunohistological study on the area postrema (AP), the subfornical organ (SFO), the organum vasculosum of the lamina terminalis (OVLT) and the median eminence (ME) in frozen brain sections from healthy SJL mice and mice suffering from EAE. Expression of cell adhesion molecules, the presence of leukocyte subpopulations and the detection of major histocompatibility complex antigen expression was compared. Similar changes were observed for all four CVOs included in this study. During EAE significantly increased numbers of CD45+ leukocytes were detected within the four CVOs investigated, the majority of which stained positive for the macrophage markers F4/80 and Mac-1. The adhesion molecules ICAM-1 and VCAM-1 were upregulated on the fenestrated capillaries within the CVOs. A considerable upregulation of MHC class I throughout the CVOs and positive immunostaining for MHC class II on perivascular cells additionally documented the immune activation of the CVOs during EAE. A significant enrichment of inflammatory infiltrates was observed in close vicinity to the CVOs. Our data indicate that the CVOs are a site for the entry of immune cells into the CNS and CSF and consequently are involved in the inflammatory process in the CNS during EAE.
Tài liệu tham khảo
Engelhardt B, Ransohoff R: The ins and outs of T cell trafficking to the central nervous system: Anatomic sites and molecular mechanisms. Trends Immunol. 2005,
Kivisakk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, Wu L, Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM: Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A. 2005, 100: 8389-94. Epub 2003 Jun 26.. 10.1073/pnas.1433000100.
Betz LA, Goldstein GW, Katzman R: Blood-Brain-Cerebrospinal Fluid Barriers. Basic Neurochemistry: Molecular, cellular, and medical aspects. Edited by: Siegel GJ. 1989, New York, Raven Press, 4th Ed.: 591-606.
Wolburg H, Wolburg-Buchholz K, Liebner S, Engelhardt B: OSP/claudin-11, claudin-1 and claudin-2 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci Lett. 2001, 13: 77-80. 10.1016/S0304-3940(01)01927-9.
Carrithers MD, Visintin I, Viret C, Janeway CSJ: Role of genetic background in P selectin-dependent immune surveillance of the central nervous system. J Neuroimmunol. 2002, 129: 51-57. 10.1016/S0165-5728(02)00172-8.
Engelhardt B, Wolburg-Buchholz K, Wolburg H: Involvement of the choroid plexus in central nervous system inflammation. Microsc Res Tech. 2001, 52: 112-129. 10.1002/1097-0029(20010101)52:1<112::AID-JEMT13>3.0.CO;2-5.
Steffen BJ, Breier G, Butcher EC, Schulz M, Engelhardt B: ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro. American Journal of Pathology. 1996, 148: 1819-1838.
Johnson AK, Gross PM: Sensory circumventricular organs and brain homeostatic pathways. FASEB J. 1993, 7: 678-686.
Leonhardt H: Ependym und zirkumventrikuläre Organe. Handbuch der mikroskopischen Anatomie des Menschen. Edited by: Oksche, A. and Vollrath L. 1980, Berlin, Springr Verlag, 177-666.
Daftar SS, Gore AC: IGF-1 in the brain as a regulator of reproductive neuroendocrine function. Exp Biol Med (Maywood). 2005, 230: 292-306.
McKinley MJ, McAllen RM, Davern P, Giles ME, Penschow J, Sunn N, Uschakov A, Oldfield BJ: The sensory circumventricular organs of the mammalian brain. Adv Anat Embryol Cell Biol. 2003, 172:III-XII: 1-122.
Gebke E, Muller AR, Jurzak M, Gerstberger R: Angiotensin II-induced calcium signalling in neurons and astrocytes of rat circumventricular organs. Neuroscience. 1998, 85: 509-520. 10.1016/S0306-4522(97)00601-5.
Engelhardt B, Laschinger M, Schulz M, Samulowitz U, Vestweber D, Hoch G: The development of experimental autoimmune encephalomyelitis in the mouse requires alpha4-integrin but not alpha4beta7-integrin. Journal of Clinical Investigation. 1998, 102: 2096-2105.
Engelhardt B, Vestweber D, Hallmann R, Schulz M: E- and P-selectin are not involved in the recruitment of inflammatory cells across the blood-brain barrier in experimental autoimmune encephalomyelitis. Blood. 1997, 90: 4459-4472.
Hallmann R, Mayer DN, Berg EL, Broermann R, Butcher EC: Novel mouse endothelial cell surface marker is suppressed during differentation of the blood-brain barrier. Developmental Dynamics. 1995, 202: 325-332.
Elmquist JK, Scammell TE, Saper CB: Mechanisms of CNS response to systemic immune challenge: the febrile response. Trends Neurosci. 1997, 20: 565-570. 10.1016/S0166-2236(97)01138-7.
Lee HY, Whiteside MB, Herkenham M: 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. 1998, 46: 495-503. 10.1016/S0361-9230(98)00045-8.
Sharshar T, Hopkinson NS, Orlikowski D, Annane D: Science review: The brain in sepsis--culprit and victim. Crit Care. 2005, 9: 37-44. Epub 2004 Sep 8.. 10.1186/cc2951.
Buller KM: Role of circumventricular organs in pro-inflammatory cytokine-induced activation of the hypothalamic-pituitary-adrenal axis. Clin Exp Pharmacol Physiol. 2001, 28: 581-589. 10.1046/j.1440-1681.2001.03490.x.
Roth J, Harre EM, Rummel C, Gerstberger R, Hubschle T: Signaling the brain in systemic inflammation: role of sensory circumventricular organs. Front Biosci. 2004, 9: 290-300.
Pedersen EB, McNulty JA, Castro AJ, Fox LM, Zimmer J, Finsen B: Enriched immune-environment of blood-brain barrier deficient areas of normal adult rats. J Neuroimmunol. 1997, 76: 117-131. 10.1016/S0165-5728(97)00038-6.
Raivich G, Banati R: Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease. Brain Res Brain Res Rev. 2004, 46: 261-281. 10.1016/j.brainresrev.2004.06.006.
Lyck R, Reiss Y, Gerwin N, Greenwood J, Adamson P, Engelhardt B: T cell interaction with ICAM-1/ICAM-2-double-deficient brain endothelium in vitro: the cytoplasmic tail of endothelial ICAM-1 is necessary for transendothelial migration of T cells. Blood. 2003, 102: 3675-83. Epub 2003 Jul 31.. 10.1182/blood-2003-02-0358.
Laschinger M, Engelhardt B: Interaction of alpha4-integrin with VCAM-1 is involved in adhesion of encephalitogenic T cell blasts to brain endothelium but not in their transendothelial migration in vitro. J Neuroimmunol. 2000, 102: 32-43. 10.1016/S0165-5728(99)00156-3.
Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N: Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992, 356: 63-66. 10.1038/356063a0.
Steffen BJ, Butcher EC, Engelhardt B: Evidence for involvement of ICAM-1 and VCAM-1 in lymphocyte interaction with endothelium in experimental autoimmune encephalomyelitis in the central nervous system in the SJL/J mouse. Am J Pathol. 1994, 145(N1): 189-201.