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bioRxiv · 10.1101/2023.06.22.546125

Serum amyloid A-dependent inflammasome activation and acute injury in a mouse model of experimental stroke

Yu, J. S.·Zhu, H.·Taheri, S.·Lee, J.-Y.·Diamond, D. M.·Kirstein, C.·Kindy, M. S.
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Abstract

BACKGROUNDSerum amyloid A (SAA) proteins increase dramatically in the blood following inflammation. Recently, SAAs are increased in humans following stroke and in ischemic animal models. However, the impact of SAAs on whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of SAA and SAA signaling in the ischemic brain. METHODSWildtype and SAA deficient mice were exposed to middle cerebral artery occlusion and reperfusion, examined for the impact of infarct volumes, behavioral changes, inflammatory markers, TUNEL staining, and BBB changes. The underlying mechanisms were investigated using SAA deficient mice, transgenic mice and viral vectors. RESULTSSAA levels were significantly increase following MCAo and mice deficient in SAAs showed reduced infarct volumes and improved behavioral outcomes. SAA deficient mice showed a reduction in TUNEL staining, inflammation and decreased glial activation. Mice lacking acute phase SAAs demonstrated a reduction in expression of the NLRP3 inflammasome and SAA/NLRP3 KO mice showed improvement. Restoration of SAA expression via SAA tg mice or adenoviral expression reestablished the detrimental effects of SAA. A reduction in BBB permeability was seen in the SAA KO mice and anti-SAA antibody treatment reduced the effects on ischemic injury. CONCLUSIONSSAA signaling plays a critical role in regulating NLRP3-induced inflammation and glial activation in the ischemic brain. Blocking this signal will be a promising approach for treating ischemic stroke. GRAPHIC ABSTRACTA graphic abstract is available for this article.

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Yu, J. S., Zhu, H., Taheri, S., Lee, J.-Y., Diamond, D. M., Kirstein, C., Kindy, M. S.. 2023-06-25. Serum amyloid A-dependent inflammasome activation and acute injury in a mouse model of experimental stroke. https://doi.org/10.1101/2023.06.22.546125

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