Disturbed function of the blood–cerebrospinal fluid barrier aggravates neuro-inflammation

Abstract

Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder, which is marked by the invasion of the central nervous system by monocyte-derived macrophages and autoreactive T cells across the brain vasculature. Data from experimental animal models recently implied that the passage of leukocytes across the brain vasculature is preceded by their traversal across the blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus. The correlation between the presence of leukocytes in the CSF of patients suffering from MS and the number of inflammatory lesions as detected by magnetic resonance imaging suggests that inflammation at the choroid plexus contributes to the disease, although in a yet unknown fashion. We here provide first insights into the involvement of the choroid plexus in the onset and severity of the disease and in particular address the role of the tight junction protein claudin-3 (CLDN3) in this process. Detailed analysis of human post-mortem brain tissue revealed a selective loss of CLDN3 at the choroid plexus in MS patients compared to control tissues. Importantly, mice that lack CLDN3 have an impaired BCSFB and experience a more rapid onset and exacerbated clinical signs of experimental autoimmune encephalomyelitis, which coincides with enhanced levels of infiltrated leukocytes in their CSF. Together, this study highlights a profound role for the choroid plexus in the pathogenesis of multiple sclerosis, and implies that CLDN3 may be regarded as a crucial and novel determinant of BCSFB integrity.

Interferon-γ Safeguards Blood-Brain Barrier during Experimental Autoimmune Encephalomyelitis

“…This is further supported by earlier reports demonstrating that TJs between ECs limit the access of soluble factors and circulating cells into the CNS, and the disruption of TJs benefits the entry of inflammatory cells into the CNS. 12,41,42 As a fundamental proinflammatory cytokine, IFNg-mediated defense of BBB integrity might dedicate to the critical guarding of immune quiescence of brain during inflammation.…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…A loss of claudin-1, -2 or -3 was observed in the choroidal epithelium in animals with experimental autoimmune encephalomyelitis or in multiple sclerosis patients [71,166]. The functional consequences of these changes on the BCSFB permeability to paracellular markers have not been explored.…”

Clinical implications of leukocyte infiltration at the choroid plexus in (neuro)inflammatory disorders

“…This localization implies that they are not available for basolateralto-apical migration of immune cells (blood-to-CSF direction), which is contradictory because large numbers of leukocytes are found in the CSF during neuroinflammation [32,33]. However, neuroinflammation can cause the loss of TJ functionality, possibly leading to the loss of CPE polarization and rearrangement of adhesion molecules [34,35]. In this way, immune cells could infiltrate from the basolateral to the apical surface via these adhesion molecules.…”