title: Inflammation induces neuro-lymphatic protein expression in multiple sclerosis brain neurovasculature.
abstract: BACKGROUND
  Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin+ (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature.
  
  
  METHODS
  We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature.
  
  
  CONCLUSIONS
  Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation.
authors.affiliation: Department of Molecular & Cellular Physiology, School of Medicine, Louisiana State University Health-Shreveport, 1501 Kings Highway, Shreveport, LA, 71130, USA. jalexa@lsuhsc.edu.
authors.forename: Ganta Vijay
authors.initials: GV
authors.lastname: Chaitanya
authors.forename: Seiichi
authors.initials: S
authors.lastname: Omura
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Sato
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Martinez
authors.forename: Alireza
authors.initials: A
authors.lastname: Minagar
authors.forename: Murali
authors.initials: M
authors.lastname: Ramanathan
authors.forename: Bianca Weinstock
authors.initials: BW
authors.lastname: Guttman
authors.forename: Robert
authors.initials: R
authors.lastname: Zivadinov
authors.forename: Ikuo
authors.initials: I
authors.lastname: Tsunoda
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Alexander
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004729:Endothelium, Lymphatic / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000096:biosynthesis*; D051379:Mice; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D025341:Principal Component Analysis; D017945:Theilovirus; D033921:Vesicular Transport Proteins / Q000032:analysis / Q000096:biosynthesis*; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; D033921:Vesicular Transport Proteins; C119248:LYVE1 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin