Inflammation induces neuro-lymphatic protein expression in multiple sclerosis brain neurovasculature

Ganta V. Chaitanya, Seiichi Omura, Fumitaka Sato, Nicholas E. Martinez, Alireza Minagar, Murali Ramanathan, Bianca W. Guttman, Robert Zivadinov, Ikuo Tsunoda, Jonathan S. Alexander

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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. Results and 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.

Original languageEnglish (US)
Article number895
JournalJournal of Neuroinflammation
StatePublished - Oct 14 2013
Externally publishedYes


  • Angiopoietin-2
  • LYVE-1
  • Podoplanin/D2-40
  • Prox-1
  • VEGF-D
  • VEGFR-3

ASJC Scopus subject areas

  • General Neuroscience
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience


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