Serum Amyloid A-Dependent Inflammasome Activation and Acute Injury in a Mouse Model of Experimental Stroke

TL;DR

This study shows that serum amyloid A (SAA) contributes to brain inflammation and injury after stroke in mice, suggesting that blocking SAA could help treat stroke.

Contribution

The study identifies SAA as a key driver of NLRP3 inflammasome activation and ischemic injury in the brain.

Findings

Mice lacking SAA had smaller infarct volumes and better behavioral outcomes after stroke.

SAA deficiency reduced inflammation, glial activation, and NLRP3 inflammasome expression.

Blocking SAA with antibodies reduced ischemic injury in mice.

Abstract

Serum amyloid A (SAA) proteins increase significantly in the blood following inflammation. Recently, SAAs were 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. Wild-type and SAA-deficient mice were exposed to middle cerebral artery occlusion and reperfusion and examined to determine 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. SAA levels were significantly increased following MCAo, and mice deficient in SAA 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 the expression of the NLRP3 inflammasome, and SAA/NLRP3 KO mice showed improvement. The restoration of SAA expression via SAA tg mice or adenoviral expression re-established the detrimental effects of SAA. A reduction in BBB permeability was seen in SAA KO mice, and anti-SAA antibody treatment reduced the effects on ischemic injury. SAA 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.

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