Abstract TMP55: TGF-β1 Induces Microglial BDNF Production and Improves Functional Outcome After Intracerebral Hemorrhage

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Abstract

Introduction: Intracerebral hemorrhage (ICH) results in the activation of microglia. Microglia can become classically activated, promoting neurotoxicity or alternatively activated, promoting tissue repair. Our lab has previously shown that microglia become alternatively activated between 3 and 14 days after ICH. This transition is critical to recovery, yet the mechanism is unknown. The anti-inflammatory cytokine TGF-β1 has a critical role in microglial development and homeostasis. We hypothesize that TGF-β1 is the mediator of microglia alternative activation after ICH and that TGF-β1 promotes microglial secretion of BDNF to promote tissue repair.

Methods: Primary microglial cultures from C57BL/6 (WT) P0-P2 pups were used to study the mechanism of alternative activation. Microglia were activated with thrombin with or without TGF-β1 for 8 and 24 hours. BDNF was measured by intracellular cytokine staining (ICS) (flow cytometry) and ELISA from cell supernatants. ICH was induced by injecting 25ul of whole blood into the right striatum of male WT mice. Mice were treated with either 10ng TGF-β1 or PBS intracerebrally immediately prior to blood injection to target microglia. Behavioral outcomes were measured by cylinder test and beam walking. Brains were harvested at 7 days for immunohistochemistry (IHC).

Results: Primary microglia that were activated with thrombin and TGF-β1 had more BDNF+ cells by ICS at 8 hours and secreted more BDNF by ELISA at 24 hours compared to thrombin alone in vitro (fig 1). Mice treated with TGF-β1 had better functional outcomes by cylinder test and beam walking than PBS treated mice 24 hours after ICH. TGF-β1 treated mice had significantly more BDNF+ CD11b+ cells (microglia/macrophages) than PBS treated 7 days after ICH by IHC.

Conclusions: TGF-β1 treatment induces microglial BDNF production and improves functional outcomes 24 hours after ICH. Ongoing work will determine whether microglial BDNF production is the link to improved outcomes.

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