Abstract
BackgroundMultiple 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.MethodsWe 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 conclusionsIntense 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.
Highlights
Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation
The purpose of this study was to investigate the role 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, and vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons in MS pathogenesis
Neuro-lymphatic proteins in postmortem RRMS brain and RRMS and SPMS sera Expression of neuro-lymphatic proteins in postmortem MS brain Western blot analysis showed significant increase in the levels D2-40 (P=0.04), LYVE-1 (P=0.018), Prox-1 (P=0.046), VEGF-D (P=0.011), and Ang-2 (P=0.01) were observed in RRMS samples compared to controls
Summary
Podoplanin+ (lymphatic marker) T helper (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 expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature. The availability and validation of novel lymphatic marker proteins (podoplanin/D2-40, LYVE-1, VEGFR-3, VEGF-D, Ang-2) and transcription factors (Fox-C2, Prox-1) [33,34,35,36] have rapidly expanded our understanding of lymphatics and allow investigation of their roles in MS pathophysiology. While LYVE-1, podoplanin, and FoxC2 are lymphatic-specific, Prox-1, VEGFR-3, VEGF-D, and Ang-2 participate in neuronal function and development [37,38,39,40,41,42]
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