The role of TLR4-dependent sterile inflammation in mediating adverse outcomes after SAH

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Abstract/Summary: Subarachnoid hemorrhage affects 40,000 Americans in the prime of their lives; half of them will die in 12 months, and one third of the survivors will have a poor cognitive outcome. The only treatments we can offer these patients in the Neuro-ICU are securing the aneurysm with a clip or coils and giving them a 32-year-old drug called nimodipine. Neither of these treatments addresses the red blood cell-induced cerebral inflammatory response which persists. Our preliminary, as well as published, data establish a role for TLR4 and microglia individually. In this proposal we will be investigating the function of cell specific TLR4 within the innate immune system. Specifically, we have created 2 novel conditional knockouts of TLR4 on microglia and myeloid cells. We will measure fever, neuronal apoptosis, hematoma clearance, and cognitive outcome in these novel conditional knockout mice to determine the extent to which the tissue resident macrophage versus neutrophil affects these outcomes. Furthermore, we will also be examining the in vivo effects of lack of TLR4 on inflammatory and apoptotic pathways using western blot and pharmacological inhibitors of TLR4-dependent inflammation. To our knowledge, the role of TLR4 in hematoma resolution has not been examined, let alone in a cell-specific manner, nor have cerebral inflammatory and apoptotic signal transduction pathways in these novel conditional knockouts. Based on our findings, novel strategies to tip the balance between TLR4-dependent inflammation and apoptotic inhibition may be exploited. Additionally, our preliminary data indicates that TLR4 might have a role in hematoma clearance; a cell-specific strategy might be employed to decrease hematoma burden and abrogate the RBC-induced cerebral inflammatory response.