Emerging Roles of Endothelial Cells in Multiple Sclerosis Pathophysiology and Therapy

Abstract

Multiple sclerosis (MS) is increasingly being viewed and studied not only as an immune-mediated demyelinating and neurodegenerative disease of the human central nervous system (CNS) but as a vascular-based form of neuroinflammation. Irrespective of the MS type (relapsing-remitting (RRMS, 85%), secondary progressive (SPMS, 12%), primary progressive (PPMS, 3%), or progressive-relapsing (PRMS, <1%)), the complex pathogenesis of MS can only be appreciated when and if vascular contributions are recognized as a significant part of MS etiology. Indeed, many novel therapies for MS target the mechanistically relevant vascular inflammatory features of these conditions and implicate cerebrovascular endothelial cells (CECs) as the “failing gatekeeper” of the blood-brain barrier (BBB). CEC and their metabolically and biochemically coupled cells (astrocytes, glia and neurons) establish and regulate several types of intercellular junctions which isolate the circulation from the brain as the functional neuro- and gliovascular units of the BBB. In health, the BBB generally isolates the brain parenchyma from immune cells and blood-borne neurotransmitters (glutamate, norepinephrine, serotonin) controlling solute exchange into and out of the CNS by a system of pumps, channels, and pores, requiring a continuous and significant energy expenditure.

Binding interactions between leukocytes and activated CEC (like non-BBB endothelial cells) can initiate and regulate trans-BBB immune cell penetration of the CNS during routine immune reconnaissance. The inappropriate intensification of these responses appears to be central to MS pathogenesis (and contributes to other neuroinflammatory diseases, acute demyelinating encephalomyelitis [ADEM], optic neuritis/Devic’s disease). Extravasation of activated and committed leukocytes across the CEC into the protected environment of the brain is the first step in generating MS lesions. All forms of MS show propagation of immune cascades culminating in the white matter demyelination and expansion of “scar” tissue (hence the term sclerosis). These regions of tissue destruction are revealed diagnostically by magnetic resonance imaging (MRI) of the brain and spinal cord as T1 and T2 hypointensities reflecting demyelination and gray matter injury, respectively.

Basic scientific and clinical studies now support contributions of vascular and endothelial cell stress and apoptosis as significant features of MS and help explain how blockade of leukocyte binding and transendothelial extravasation of activated immune cells across the MS-inflamed cerebral microvasculature and restitution of endothelial barrier function represent important goals of MS treatment. Such approaches can achieve significant reductions in MS disease activity and progression, but carry risks from interference with immune surveillance. Endothelial stress in the forms of endothelial cell-derived microparticles (EMPs) is also becoming increasingly recognized, with EMPs acting as both markers and mediators of MS pathology. In this chapter, we review recent findings and advances regarding leukocyte-endothelial interactions at the BBB and how the BBB can be manipulated to treat MS.