| First Author | Thom SR | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 44 | Pages | 18312-18324 |
| PubMed ID | 28972154 | Mgi Jnum | J:249808 |
| Mgi Id | MGI:5920482 | Doi | 10.1074/jbc.M117.802629 |
| Citation | Thom SR, et al. (2017) Neutrophil microparticle production and inflammasome activation by hyperglycemia due to cytoskeletal instability. J Biol Chem 292(44):18312-18324 |
| abstractText | Microparticles are lipid bilayer-enclosed vesicles produced by cells under oxidative stress. MP production is elevated in patients with diabetes, but the underlying cellular mechanisms are poorly understood. We hypothesized that raising glucose above the physiological level of 5.5 mm would stimulate leukocytes to produce MPs and activate the nucleotide-binding domain, leucine-rich repeat pyrin domain-containing 3 (NLRP3) inflammasome. We found that when incubated in buffer with up to 20 mm glucose, human and murine neutrophils, but not monocytes, generate progressively more MPs with high interleukin (IL)-1beta content. Enhanced MP production required generation of reactive chemical species by mitochondria, NADPH oxidase, and type 2 nitric-oxide synthase (NOS-2) and resulted in S-nitrosylation of actin. Depleting cells of capon (C-terminal PDZ ligand of neuronal nitric-oxide synthase protein), apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain (ASC), or pro-IL-1beta prevented the hyperglycemia-induced enhancement of reactive species production, MP generation, and IL-1beta synthesis. Additional components required for these responses included inositol 1,3,5-triphosphate receptors, PKC, and enhancement of filamentous-actin turnover. Numerous proteins become localized to short filamentous actin in response to S-nitrosylation, including vasodilator-stimulated phosphoprotein, focal adhesion kinase, the membrane phospholipid translocation enzymes flippase and floppase, capon, NLRP3, and ASC. We conclude that an interdependent oxidative stress response to hyperglycemia perturbs neutrophil cytoskeletal stability leading to MP production and IL-1beta synthesis. |
