Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain

Charlotte Schmitt,Jean-François Ghersi-Egea,Nathalie Strazielle

doi:10.1186/1742-2094-9-187

Abstract

BackgroundCerebrospinal fluid (CSF) has been considered as a preferential pathway of circulation for immune cells during neuroimmune surveillance. In order to evaluate the involvement of CSF-filled spaces in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, we performed a time-course analysis of immune cell association with the CSF-containing ventricles, velae, and cisterns in two active models of this disease.MethodsGuinea-pig spinal cord homogenate-induced EAE in rat and myelin oligodendrocyte glycoprotein-induced EAE in mouse were used. Leukocyte distribution and phenotypes were investigated by immunohistochemistry in serial sections of brain areas of interest, as well as in CSF withdrawn from rat. Immune cells associated with the choroid plexuses were quantified.ResultsFreund’s adjuvant-induced peripheral inflammation in the absence of brain antigen led to a subtle but definite increase in the number of myeloid cells in the extraventricular CSF spaces. In both rats and mice, EAE was characterized by a sustained and initial infiltration of lymphocytes and monocytes within forebrain/midbrain fluid-filled compartments such as the velum interpositum and ambient cisterns, and certain basal cisterns. Leukocytes further infiltrated periventricular and pericisternal parenchymal areas, along perivascular spaces or following a downward CSF-to-tissue gradient. Cells quantified in CSF sampled from rats included lymphocytes and neutrophils. The distinctive pattern of cell distribution suggests that both the choroid plexus and the vessels lying in the velae and cisterns are gates for early leukocyte entry in the central nervous system. B-cell infiltration observed in the mouse model was restricted to CSF-filled extraventricular compartments.ConclusionThese results identified distinctive velae and cisterns of the forebrain and midbrain as preferential sites of immune cell homing following peripheral and early central inflammation and point to a role of CSF in directing brain invasion by immune cells during EAE.

Highlights

Cerebrospinal fluid (CSF) has been considered as a preferential pathway of circulation for immune cells during neuroimmune surveillance
The Blood-brain barrier (BBB) localizes at the endothelium of brain microvessels and the Blood-cerebrospinal fluid barrier (BCSFB) is formed by the epithelium of the choroid plexuses (CP)
T cells identified as CD3+ cells amounted to 60% of total leukocytes in the blood of control rats (Figure 1A), while MPO+/CD68- neutrophils represented less than 10% of leukocytes (Figure 1B)

Summary

Introduction

Cerebrospinal fluid (CSF) has been considered as a preferential pathway of circulation for immune cells during neuroimmune surveillance. Cerebrospinal fluid (CSF) has been proposed to constitute a predominant route of T-cell trafficking to and from the CNS during physiological neuroimmune surveillance in humans [3,4]. The constitutive expression of P-selectin and the chemokine CCL20 in CP have pointed out the BCSFB as a direct route of lymphocyte migration from the blood into the brain [8,9,10]. This route accounts for the lack of permissivity of the resting brain endothelium to immune cell migration during neuroinflammation initiation. Other studies rather proposed that the vessels running in subarachnoid spaces of the lower part of the spinal cord were the initial site of T-cell entry into the CSF during EAE in rat, implying that EAE is primarily a spinal cord disease [11]

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Conclusion