Abstract T P71: Meningeal-Derived IL-6 Exacerbates Post-Stroke Inflammation and Pathology

Abstract

Background: 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 (KitW/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.