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

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.

Influx and Efflux of Immune Cells in the Central Nervous System

“…VEGF-D is also one of the most potent lymphangiogenic factors [18] and plays an important role in neuronal synaptic activity, dendritic length, and dendrite arborization [19]. We observed the alteration of VEGF-D expression levels in EAE/MS settings [16]. These observations indicate that CNS neuroinflammatory diseases alter neuro-lymphatic protein expressions that are involved in the clearance of fluids from the CNS diseases [20,21].…”

“…In addition, regarding the immune cell efflux from the CNS, we have identified altered expressions of lymphatic molecules such as LYVE-1, VEGF-D, etc. [16]. Here, LYVE-1 is suggested to be involved in lymph angiogenesis [17].…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…Through control of lymphoid chemokine production in epithelial and fibroblastic stromal cells, IL‐22 also drives lymphoid neogenesis in mice following salivary gland cannulation with adenovirus 23. Podoplanin and IL‐17 have also been linked with ectopic lymphoneogenesis in human diseases 21, 24, 25…”

Anatomy and roles of lymphatics in inflammatory diseases

“…However, as previous studies by Chaitanya et al showed for the first time that lymphatic molecules, present in serum (and apparently originating within the CNS), could be used to distinguish healthy individuals from those with remitting-relapsing MS versus secondary progressive MS, it is anticipated that CNS lymphatics/glymphatics might represent appropriate targets in forms of neuroinflammation and neurodegeneration. 162 Further studies to determine when the activation, regulation and remodeling of such lymphatic networks are adaptive and can be exploited as innovative therapeutic, diagnostic and prognostic targets are clearly warranted, and are not limited to settings of IBD, myocardial and CNS disturbances with applications in nearly all organ systems. 112,157,163 …”