Myeloperoxidase loss protects against delayed cerebral injury after subarachnoid hemorrhage
bioRxiv(2019)
Abstract
Background: Neutrophil infiltration into the central nervous system (CNS) after aneurysmal subarachnoid hemorrhage (SAH) is critical to the development of delayed cerebral injury (DCI). The goal of the present study is to characterize the neutrophil activity that leads to DCI. Methods: We tested mice deficient in elastase, NADPH oxidase, or myeloperoxidase (MPO) in our SAH model for delayed spatial memory changes and vascular constriction associated with DCI. Because the MPO mouse showed no DCI, we focused on the MPO null mice, including experiments to reconstitute the MPO effect by injection of active MPO and its substrate, H2O2. Flow cytometry and immunohistochemistry were used to determine the temporal and spatial location of neutrophils and glial cells in the CNS after SAH in WT and MPO null mice. Results: Following SAH, neutrophils infiltrate the outer meninges from outside the CNS in a delayed fashion. Mice with functional deletion of the neutrophil effector molecule myeloperoxidase (MPO KO) do not develop DCI. Re-introduction of biologically active MPO to the meninges, i.e. CSF, of MPO KO mice at the time of the hemorrhage restores the spatial memory deficit seen in DCI. However, addition of active MPO to the CSF of wildtype mice (WT) without hemorrhage does not lead to DCI, suggesting that blood components and MPO are necessary to cause DCI in our model. The localization of neutrophils, exclusively in the meninges, suggests that their effect on spatial memory goes through intermediate cells (presumably glia). Astrocyte reactivity increases in WT after SAH but not in MPO KO mice, suggesting that astrocytes mediate the effects of neutrophil-derived MPO on neurons in the brain parenchyma after SAH. Conclusions: These results demonstrate that neutrophils can modulate cognition from the meninges, and that immune cell reactivity in the meninges can modulate spatial memory through indirect effects on neurons.
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Key words
Innate Inflammation,meninges,neuronal activity,astrocytes,cognitive deficits
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