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Granzyme b : role in spinal cord injury and impeded repair Oram, Cameron Paul

Abstract

The inflammatory cascade following spinal cord injury (SCI) involves multiple cellular and molecular responses that can both aid and impede recovery. A large component of the wound response is the infiltration of immune cells that secrete pro-inflammatory cytokines and proteases. Granzyme B (GzmB) is a serine protease released by immune cells that negatively affects wound healing through its intracellular and extracellular protease activity. GzmB is abundant in neuroinflammatory conditions and contributes to neuron and oligodendrocyte cell death. In this study we investigate the role of GzmB in tissue injury, inflammation and functional recovery following SCI. An SCI was induced in wild-type (WT) and GzmB knockout (GzmB-KO) mice at thoracic level 9. Mouse locomotion was observed over the course of 6 weeks using three behaviour tests (Basso mouse scale, rotarod and horizontal ladder). Lesions were harvested for histological analysis and sections stained with markers for neurons (NeuN) and dyed for myelin (Eriochrome Cyanine). A second cohort of mice were maintained for 1 week after SCI and probed for GzmB expression and cellular localization. GzmB expression was probed using markers for macrophages or microglia (CD68). GzmB-KO mice exhibited significantly improved motor scores, increased myelin and neural survival compared to WT controls. GzmB expression was observed in macrophages at 7 days post injury. In summary, GzmB is elevated and contributes to neurotoxicity, demyelination and impaired functional recovery following SCI.

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