Serum Amyloid A-Mediated Inflammasome Activation of Microglial Cells in Cerebral Ischemia.

Abstract

Serum amyloid A (SAA) proteins are acute-phase reactant associated with high-density lipoprotein (HDL) particles and increase in the plasma 1000-fold during inflammation. Recent studies have implicated SAAs in innate immunity and various disorders; however, the precise mechanism eludes us. Previous studies have shown SAAs are elevated following stroke and cerebral ischemia, and our studies demonstrated that SAA-deficient mice reduce inflammation and infarct volumes in a mouse stroke model. Our studies demonstrate that SAA increases the cytokine interleukin-1β (IL-1β), which is mediated by Nod-like receptor protein 3 (NLRP3) inflammasome, cathepsin B, and caspase-1 and may play a role in the pathogenesis of neurological disorders. SAA induced the expression of NLRP3, which mediated IL-1β induction in murine BV-2 cells and both sex primary mouse microglial cells, in a dose- and time-dependent fashion. Inhibition or KO of the NLRP3 in microglia prevented the increase in IL-1β. N-acetyl-l-cysteine and mito-TEMPO blocked the induction of IL-1β by inhibiting ROS with SAA treatment. In addition, inhibition of cathepsin B with different drugs or microglia from CatB-deficient mice attenuated inflammasome activation. Our studies suggest that the impact of SAA on inflammasome stimulation is mediated in part by the receptor for advanced glycation endproducts and Toll-like receptor proteins 2 and 4. SAA induced inflammatory cytokines and an M1 phenotype in the microglial cells while downregulating anti-inflammation M2 phenotype. These studies suggest that brain injury to can elicit a systemic inflammatory response mediated through SAA that contributes to the pathological outcomes.SIGNIFICANCE STATEMENT In the present study, serum amyloid A can induce that activation of the inflammasome in microglial cells and give rise to IL-1β release, which can further inflammation in the brain following neurological diseases. The also presents a novel target for therapeutic approaches in stroke.

• Authors: Jin Yu, Hong Zhu, Saeid Taheri, William Mondy, Leonardo Bonilha, Gayenell S Magwood, Daniel Lackland, Robert J Adams, Mark S Kindy
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 39 Issue 47 Pg. 9465-9476 (11 20 2019) ISSN: 1529-2401 [Electronic] United States
• PMID: 31611307 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 the authors.

Chemical References

• Inflammasomes
• Inflammation Mediators
• Serum Amyloid A Protein

Topics

• Animals
• Brain Ischemia (metabolism, pathology)
• Female
• Inflammasomes (metabolism)
• Inflammation Mediators (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microglia (drug effects, metabolism, pathology)
• Serum Amyloid A Protein (toxicity)