Abstract TP100: Meningeal Mast Cells Can Exacerbate Stroke Pathology In Mice

Abstract

Inflammation critically contributes to post-stroke brain damage. Mast cells (MCs), perivascular cells best known as effector cells involved in the development of inflammatory processes, have been reported to exacerbate stroke pathology. Unlike other immune cells, mature MCs do not circulate but are resident in virtually all anatomical sites, including brain parenchyma and meninges. Thus a key question is which tissue-specific MCs are important after stroke. To address this, we used ‘mast cell knock-in’ mouse models whereby genetically MC-deficient mice were selectively repaired of their MC deficiency by engraftment of in vitro grown mast cells. Methods: Two different MC-deficient mouse models (KitW-sh/W-sh and KitW/W-v) were used. For each model, 3 groups were tested: wild-type, MC-deficient, and MC-engrafted. Mice were subjected to 30 min occlusion of the middle cerebral artery. Brain swelling and infarct size were assessed by T2-weighted MRI and histology. The immune response was quantified by flow cytometry. Results: MC-deficient mice had less brain swelling at 3d post-stroke, and smaller lesions at 3d and 2wk post-stroke than their corresponding wild-type or systemically MC-engrafted groups, implying that MCs exacerbate ischemic injury. MC-deficient mice also had fewer brain granulocytes at 3d post-stroke compared to the other two groups. However, no MC-dependent changes in granulocyte numbers in blood and spleen were observed at 3d, suggesting a role for central nervous system (CNS) MCs in modulating granulocyte trafficking to the brain and stroke pathology. Analysis of the CNS MC distribution in wild-type and MC-engrafted mice revealed equivalent numbers of MCs in meninges in both groups but almost no MCs in brain parenchyma of MC-engrafted groups. This suggests that meningeal MCs, rather than parenchymal MCs, are key effectors of stroke pathology. To test this, MCs were engrafted locally into the meninges. These meningeal MC-engrafted mice had significantly more brain swelling, larger infarcts, and more brain granulocytes after stroke than MC-deficient mice. Conclusions: Our results support the conclusion that meningeal MCs can exacerbate stroke pathology. Hence, targeting these cells may be a novel therapeutic strategy for stroke.