Stroke Therapy

Stroke injury initiates a cascade of inflammatory events including immune cell infiltration into the brain. This post-stroke inflammation is a critical determinant of damage and recovery after stroke and understanding the interplay between the immune system and the brain after stroke holds much promise for therapeutic intervention.

An understudied but important aspect of this interplay is the role of the meninges, the three membranes (the dura mater, arachnoid, and pia mater) that cover the brain and spinal cord (Figure 1). The meninges have long been recognized as an anatomical barrier protecting the central nervous system (CNS). However, accumulating evidence suggests that the meninges are important for communication between the CNS and immune system during health and disease. All blood vessels pass through the meningeal subarachnoid space before entering the brain and this vascular connection, as well as the close proximity of the meninges to the underlying parenchymal nervous tissue, make them ideally located to act as a gatekeeper modulating immune cell trafficking to the CNS.

Our work focused on the role of meningeal-located mast cells in controlling post-stroke brain inflammation and pathology (reference our Arac A et al. AJP paper). Mature mast cells (MCs), unlike other immune cells, do not circulate but are resident in virtually all vascularized tissues, including brain and meninges, where they can be activated to release a diverse array of mediators including cytokines. As such, MCs, which are best known as pro-inflammatory effector cells, are critical in the development of inflammatory processes in many pathologies. Using genetic and cell transfer approaches in mice, we showed that MCs contribute to key features of stroke pathology, including infiltration of granulocytes and macrophages, brain swelling, and infarct size (Figure 2), and that this was dependent on MC-secretion of IL-6. Importantly, MCs in the meninges, rather than the brain parenchyma, were necessary and sufficient to illicit this response. Microarray analysis of the meninges revealed that MCs enhanced the expression of genes related to the inflammatory/immune response after stroke. Understanding how the MCs are activated after stroke, and the downstream molecular pathways activated by the MCs are key next steps in understanding the inflammatory response after stroke.

Figure 1: Schematic how the brain is enveloped by the meninges that contain mast cells in both the dura mater and pia mater. Before entering the brain parenchyma, blood vessels course on the surface of the brain between the dura mater and pia mater. Therefore, as a resident immune cell in the meninges, the MC has the potential to influence blood vessels and to function as a ‘gatekeeper’ to influence brain inflammation and pathology.

Figure 2: Evidence that meningeal MCs are sufficient to enhance pathology after stroke. (A) Representative T2W-MRI images, and quantification of (B) brain swelling, (C) infarct size, and numbers of (D) granulocytes and macrophages in brain 3 d after stroke in MC-deficient (KitW/W-v) mice and the corresponding wild-type mice and meningeal MC-engrafted KitW/W-v mice. *P<0.05, **P<0.01, ***P<0.005. Data are shown as mean±sem.

Significance: These data reveal a novel role for MCs in the meninges as potential gatekeepers for modulating post-stroke brain inflammation and pathology. The relative accessibility of the meninges could offer a new therapeutic option (e.g. intrathecal immunotherapy) that may overcome the hurdle of targeting drugs to the injured brain and reduces side effects associated with systemic immunomodulation.