Introduction: Inflammation critically contributes to post-stroke brain damage and consequently there is much interest in factors that influence stroke-induced brain inflammation. Interleukin 6 (IL-6) has been heralded as an important predictor of stroke outcome, however there are conflicting reports describing detrimental, beneficial and even no effects of IL-6 on stroke pathology. This has led to the suggestion that the post-stroke effects of IL-6 may be dependent on its cellular location. We report that IL-6 produced by meningeal resident mast cells (pro-inflammatory effector cells) significantly exacerbates brain inflammation and pathology after stroke. These are the first data to identify the role in stroke pathology of IL-6 derived from a specific cell type in a particular anatomic location in vivo.
Methods: A mast cell (MC) ‘knock-in’ mouse model was used where MC-deficient mice (Kit W/W-v) were repaired of their MC deficiency by engraftment of in-vitro-derived MCs. MCs from wild-type (WT) or IL-6 knock-out mice were engrafted into the meninges. Mice were subjected to 30 min middle cerebral artery occlusion. Brain swelling and infarct size were assessed by T2-weighted MRI and histology. The immune response was quantified by flow cytometry.
Results: CNS distribution analysis of MCs in wild-type and MC-engrafted mice revealed equivalent numbers of MCs in meninges in all groups but almost no MCs in brain parenchyma of the MC-engrafted groups. At 3d post-stroke, wild-type mice and MC-deficient mice engrafted with WT MCs exhibited significantly greater brain swelling, larger infarcts, and more brain granulocytes and activated macrophages than MC-deficient mice. These findings indicate that meningeal MCs exacerbate stroke outcome. In contrast, the pathology in IL6-KO MC-engrafted mice resembled that in MC-deficient mice, with significantly less brain swelling, smaller infarcts and fewer granulocytes and activated macrophages than in the WT MC-engrafted mice. This indicates that MC-secreted IL-6 contributes importantly to the detrimental effects of MCs.
Conclusions: IL-6 produced by mast cells in the meninges is detrimental to stroke outcome. Thus, intrathecal targeting of meningeal inflammation may offer a novel therapeutic strategy for stroke.
Patient Care: It highlights a novel role of the meninges in modulating brain inflammation after stroke and suggests that intrathecal targeting of meningeal inflammation may offer a novel therapeutic strategy for stroke.
Learning Objectives: By the conclusion of this session, participants should: 1) Recognize that the meninges modulates post-stroke inflammation and brain pathology, 2) understand that mast cells that reside in the meninges play an important role in this modulatory role of the meninges after stroke, 3) understand that detrimental effect of meningeal mast cells after stroke is mediated , at least in part, by their secretion of IL-6, and 4) appreciate that intrathecal targeting of meningeal mast cells may offer a novel therapy for stroke.