Meningeal Mast Cells Affect Early T Cell Central Nervous System Infiltration and Blood-Brain Barrier Integrity through TNF: A Role for Neutrophil Recruitment?

Abstract

Mast cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis, a rodent model of the human demyelinating disease multiple sclerosis. Yet their site and mode of action is unknown. In both diseases, myelin-specific T cells are initially activated in peripheral lymphoid organs. However, for disease to occur, these cells must enter the immunologically privileged CNS through a breach in the relatively impermeable blood-brain barrier. In this study, we demonstrate that a dense population of resident mast cells in the meninges, structures surrounding the brain and spinal cord, regulate basal CNS barrier function, facilitating initial T cell CNS entry. Through the expression of TNF, mast cells recruit an early wave of neutrophils to the CNS. We propose that neutrophils in turn promote the blood-brain barrier breach and together with T cells lead to further inflammatory cell influx and myelin damage. These findings provide specific targets for intervention in multiple sclerosis as well as other immune-mediated CNS diseases.

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

“…Intravenous or intracranial injection of BMMCs has been recently found to restore the pool of meningeal MCs in Kit W/W-v mice, leading to the recovery of a WT-like disease course and to the rescue of neutrophil infiltration in the CNS. 20 In our system, although detecting scattered MCs in Kit þ / þ mice in the context of the reticulum formed by the arachnoid, the subdural neurothelium, and the dura mater, in line with previous observations, 29 we could not find MCs populating the [45][46][47] in Kit W-sh/W-sh mice, without finding any difference, according to previous data. 29 However, we cannot exclude that DC-expressed c-Kit has some role on immunization, as demonstrated in a model of allergic asthma, in which Ag/adjuvant exposure induced on DCs the expression of both c-Kit and its ligand, promoting Th2 and Th17 responses.…”

“…However, our results are in contrast with a recent report from the same group, showing decreased EAE symptoms in Kit W/W-v mice compared with Kit þ / þ mice also on the application of a relatively milder immunization protocol (100 mg of MOG and 250 ng of PTX). 20 Thus, the discrepancies between our results and those reported by the Brown's group remain to be fully understood. However, it is possible that the opposite results observed in Kit W/W-v under different immunization protocols are related to a differential impact of the same mutation on distinct pathological mechanisms depending on the quality/quantity of the immune stimulation and on experimental conditions.…”

“…16,38 In their system, MC systemic reconstitution restored disease severity by recovering an efficient encephalitogenic T-cell response in peripheral lymphoid organs 18 and by restoring neutrophil penetration at the blood-brain barrier. 20 Our results reconciled, in part, the apparently contrasting findings in the two MC-deficient strains. Indeed, we could reproduce Brown's data in the Kit W/W-v model when a strong immunization protocol was applied, but under milder conditions, which are our standard procedure to induce active EAE, 48 Kit W/W-v mice developed an exacerbated rather than an attenuated disease, replicating our results in the Kit W-sh/W-sh model.…”

“…19 In Kit W/W-v mice, MCs have also extra-lymphoid roles in EAE, favoring the access of neutrophils to inflamed CNS by secreting TNF in meninges. 20 In contrast to these previous works, Bennett et al 21 have recently shown that MCs are dispensable for EAE development in both Kit W/W-v and Kit W-sh/W-sh models. Conversely, Stelekati et al 22 have recently published that EAE severity is decreased in Kit W-sh/W-sh mice but is restored following MC knockin, 22 thus confirming the data obtained by Brown and colleagues in Kit W/W-v model.…”

“…On the contrary, in the Kit W/W-v model, the failure to correct peripheral neutropenia with BMMC reconstitution suggests a neutrophil-intrinsic role of the Kit W/W-v mutation in shaping the granulocyte compartment. 20 It could be proposed that, in Kit W-sh/W-sh mice, MCs may actively inhibit granulopoiesis by unknown mechanisms, or passively limit excessive myeloid expansion simply by sequestering the majority of locally available, paracrine or juxtacrine, SCF through the highly expressed c-Kit receptor. This observation suggests to carefully interpret the data obtained in MC-knockin experimental systems, as also non-MC-related defects may be corrected by MC transfer.…”