Abstract 12527: Serum Amyloid A, Inflammasome Activation and Stroke

Abstract

Serum amyloid A (SAA) proteins are critical to the regulation of inflammation in systemic as well as neurological diseases. Studies have shown that during an acute phase response (APR), SAA levels increase 1000-fold and can stimulate the inflammasome, trigger the recruitment of immune cells to inflammatory sites, and elicit the induction of enzymes that degrade extracellular matrix. Our long-term goal is to dissect the mechanisms regulating SAA function, particularly the contribution to stroke related damage. Recent studies have demonstrated that activation of the inflammasome is a critical event in stroke progression in mice. The central hypothesis is that SAA activates the NLRP3 inflammasome, and amplifying the local inflammatory responses that enhance neuronal cell death and stroke progression. We show that activation of the NLRP3 inflammasome by SAA exacerbates stroke in mice. Using mice deficient in SAA, RAGE and various inflammasome components (cathepsin B, NLRP3, ASC, caspase-1 and IL-1beta) or IL-1R mice, we demonstrated that SAA-mediated stroke outcomes are dependent on the NLRP3 inflammasome. In addition, using microglial cell cultures, we determined the impact of SAA on RAGE mediated pathologies (ROS generation, etc.) as well as the influence of SAA-HDL on SAA-mediated NLRP3 activation. We tested the hypothesis that systemic SAA exacerbates the progression of neuronal cell death and inflammation in stroke. We showed that SAA deficient mice determined the impact on stroke infarct volume and outcomes. In addition, using viral vectors to express SAA as well as an inducible transgene help us determine the role of SAA with specific expression of SAA. The impact of SAA on inflammation, neuronal cell death, matrix remodeling, etc. was attenuated in SAA deficient mice. In addition, we demonstrated the role of SAA and the inflammasome in human stroke, and the relationship between plasma SAA, IL-1beta and the impact on stroke outcomes.