Image_1_Mitochondrial DNA Promotes NLRP3 Inflammasome Activation and Contributes to Endothelial Dysfunction and Inflammation in Type 1 Diabetes.TIF
Background: NLRP3 inflammasome activation in response to several signals, including mitochondrial DNA (mDNA), regulates inflammatory responses by caspase-1 activation and interleukin-1β (IL-1β) release. Circulating mDNA is linked to micro and macrovascular complications in diabetes. However, a role for mDNA in endothelial dysfunction is not clear. We tested the hypothesis that mDNA contributes to diabetes-associated endothelial dysfunction and vascular inflammation via NLRP3 activation.
Methods: Vascular reactivity, reactive oxygen species (ROS) generation, calcium (Ca2+) influx and caspase-1 and IL-1β activation were determined in mesenteric resistance arteries from normoglicemic and streptozotocin-induced diabetic C57BL/6 and NLRP3 knockout (Nlrp3–/–) mice. Endothelial cells and mesenteric arteries were stimulated with mDNA from control (cmDNA) and diabetic (dmDNA) mice.
Results: Diabetes reduced endothelium-dependent vasodilation and increased vascular ROS generation and caspase-1 and IL-1β activation in C57BL/6, but not in Nlrp3–/– mice. Diabetes increased pancreatic cytosolic mDNA. dmDNA decreased endothelium-dependent vasodilation. In endothelial cells, dmDNA activated NLRP3 via mitochondrial ROS and Ca2+ influx. Patients with type 1 diabetes exhibited increased circulating mDNA as well as caspase-1 and IL-1β activation.
Conclusion: dmDNA activates endothelial NLRP3 inflammasome by mechanisms that involve Ca2+ influx and mitochondrial ROS generation. NLRP3 deficiency prevents diabetes-associated vascular inflammatory damage and endothelial dysfunction. Our study highlights the importance of NLRP3 inflammasome in diabetes-associated vascular dysfunction, which is key to diabetic complications.
History
References
- https://doi.org//10.1016/j.neuroscience.2018.01.067
- https://doi.org//10.4049/jimmunol.170.6.3029
- https://doi.org//10.3389/fimmu.2017.00164
- https://doi.org//10.1016/j.bbrc.2018.03.142
- https://doi.org//10.1016/j.bbamcr.2014.11.012
- https://doi.org//10.1189/jlb.0309164
- https://doi.org//10.1189/jlb.0703328
- https://doi.org//10.1016/j.ebiom.2015.04.002
- https://doi.org//10.1016/s0140-6736(96)90013-6
- https://doi.org//10.1007/s10753-016-0483-3
- https://doi.org//10.1158/1055-9965.EPI-14-0471
- https://doi.org//10.1016/j.freeradbiomed.2012.09.026
- https://doi.org//10.1016/j.bbadis.2017.07.025
- https://doi.org//10.1007/s001250051258
- https://doi.org//10.1038/nrneph.2014.116
- https://doi.org//10.1159/000074047
- https://doi.org//10.1038/327077a0
- https://doi.org//10.1016/s0014-5793(97)01273-8
- https://doi.org//10.1111/jdi.12366
- https://doi.org//10.1016/j.bbrc.2015.10.105
- https://doi.org//10.7314/apjcp.2015.16.18.8299
- https://doi.org//10.1016/j.diabres.2015.10.006
- https://doi.org//10.1038/nature04515
- https://doi.org//10.1093/cvr/cvv137
- https://doi.org//10.1167/iovs.15-16937
- https://doi.org//10.1161/01.res.41.1.19
- https://doi.org//10.1073/pnas.1117765109
- https://doi.org//10.1038/ni.1980
- https://doi.org//10.1016/j.cyto.2015.06.017
- https://doi.org//10.1016/j.freeradbiomed.2014.09.028
- https://doi.org//10.1038/sj.cdd.4402195
- https://doi.org//10.14744/AnatolJCardiol.2016.7209
- https://doi.org//10.1161/01.cir.103.9.1238
- https://doi.org//10.1016/j.immuni.2012.01.009
- https://doi.org//10.1016/j.prostaglandins.2015.09.004
- https://doi.org//10.1186/s12933-014-0158-z
- https://doi.org//10.1016/j.neuroscience.2011.11.062
- https://doi.org//10.1016/j.biopha.2016.11.134
- https://doi.org//10.1038/nature08780
- https://doi.org//10.1089/ars.2014.5978
- https://doi.org//10.1038/ni.1831
- https://doi.org//10.1038/nature09663
CC BY 4.0