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Despite recent studies that show oxidative stress-generated reactive oxygen species (ROS) regulate NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated innate immune response in various diabetic complications, the mechanism by which ROS activate innate immune response is not well understood. We have shown previously that aldose reductase (AR), besides reducing glucose, reduces lipid aldehydes and their glutathione conjugates and participates in various oxidative stress-induced inflammatory pathways. To understand the role of AR in ROS-induced innate immune response, we have investigated the mechanism(s) by which AR activates hyperglycemia-induced NLRP3 inflammsome-initiated innate immune response in Thp1 monocytes and in streptozotocin (STZ)-induced diabetic mice. In Thp1 monocytes, inhibition or ablation of AR prevented high-glucose-induced activation of NLRP3 inflammasome and caspase-1 and release of the innate immune cytokines interleukin (IL)-1β and IL-18. AR inhibition in Thp1 cells also prevented the high-glucose-induced generation of ROS, influx of Ca2+, efflux of K+, and activation of Lyn, Syk, and PI3K. Furthermore, the AR inhibitor fidarestat prevented the expression of NLRP inflammasome components in STZ-induced diabetic mouse heart and aorta, and also prevented the release of various cytokines in the serum. Collectively, our data suggest that AR regulates hyperglycemia-induced NLRP3 inflammasome-mediated innate immune response by altering the ROS/Lyn/Syk/PI3K/Ca2+/K+ signals.
Pubmed ID: 28938395 RIS Download
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This recombinant monoclonal targets GAPDH
View all literature mentionsThis monoclonal targets Phospho-Syk (Tyr525/526)
View all literature mentionsThis isotype control targets not applicable
View all literature mentionsThis unknown targets PI3 Kinase p85
View all literature mentionsThis polyclonal targets
View all literature mentionsThis monoclonal targets Human Lyn
View all literature mentionsThis polyclonal targets Phospho-Lyn (Tyr507)
View all literature mentionsThis polyclonal targets AKR1B1
View all literature mentionsThis polyclonal targets Nlrp3
View all literature mentionsThis polyclonal targets PYCARD
View all literature mentionsThis polyclonal targets IL-18 (H-173)
View all literature mentionsThis polyclonal targets IL1B
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