Ogg1 -Dependent DNA Repair Regulates NLRP3 Inflammasome and Prevents Atherosclerosis

Abstract

Rationale Activation of NLRP3 inflammasome mediating IL-1β secretion has emerged as an important component of inflammatory processes in atherosclerosis. Mitochondrial DNA (mtDNA) damage is detrimental in atherosclerosis and mitochondria are central regulators of the NLRP3 inflammasome. Human atherosclerotic plaques express increased mtDNA damage. The major DNA glycosylase OGG1, is responsible for removing the most abundant form of oxidative DNA damage. Objective To test the role of OGG1 in development of atherosclerosis in mouse. Methods and Results We observed that Ogg1 expression decreases over time in atherosclerotic lesion macrophages of Ldlr KO mice fed a western diet. Ogg1−/−Ldlr−/− mice fed a western diet resulted in an increase in plaque size and lipid content. We found increased oxidized mtDNA, inflammasome activation, and apoptosis in atherosclerotic lesions and also higher serum IL-1β and IL-18 in Ogg1−/−Ldlr−/− mice compared with Ldlr−/−. Transplantation with Ogg1−/− bone marrow (BM) into Ldlr−/− mice led to larger atherosclerotic lesions and increased IL-1β production. However, transplantation of Ogg1−/−Nlrp3−/− BM reversed the Ogg1−/− phenotype of increased plaque size. Ogg1−/− macrophages showed increased oxidized mtDNA and had greater amounts of cytosolic mtDNA and cytochrome c, increased apoptosis, and more IL-1β secretion. Finally, we found that proatherogenic miR-33 can directly inhibit human OGG1 expression and indirectly suppress both mouse and human OGG1 via AMPK. Conclusions OGG1 plays a protective role in atherogenesis by preventing excessive inflammasome activation. Our study provides insight into a new target for therapeutic intervention based on a link between oxidative mtDNA damage, OGG1, and atherosclerosis via NLRP3 inflammasome.

Controlling Inflammation Through DNA Damage and Repair

“…Although miR33 has long been implicated in atherosclerosis, antagonism of miR33 has variable effects on both serum lipids and atherosclerosis at different time points, 16 and rodents and humans express different isoforms of miR33. As found by Tumurkhuu et al, 11 miR33 may have different targets in rodent models compared with humans.…”

“…12 However, it was not known whether oxidized mtDNA could promote atherosclerosis, and if so, how this was mediated. Here, Tumurkhuu et al 11 show that OGG1 is reduced in macrophages in atherosclerosis, and macrophages lacking OGG1 are more sensitive to oxidant stress, with increased release of cytochrome c, caspase 1 activation, NLRP3 activation, release of IL1β, and apoptosis. Low-density lipoprotein receptor (LDLR) null mice also lacking OGG1 in all tissues showed increased plaque and necrotic core areas, and reduced collagen content, with higher serum IL-1β, MCP-1 (monocyte chemoattractant protein-1), and IL-18.…”

“…9 Furthermore, chronic oxidative stress can increase 8-oxo-G levels >250-fold without apparent severe consequences. 10 Against this background, the current article by Tumurkhuu et al 11 shows that oxidative DNA damage directly results in the production of the archetypal proinflammatory cytokines interleukin (IL)1β and IL18 through the activation of NLRP3 (the NACHT, LRR, and PYD domains-containing protein 3) inflammasome, itself a major component of the innate immune system that functions as a pathogen recognition receptor that recognizes pathogen-associated molecular patterns. The NLRP3 inflammasome can also detect products of damaged cells such as extracellular ATP, crystalline uric acid, and cholesterol.…”

“…Like all excellent studies and important studies, the current article by Tumurkhuu et al 11 raises some important questions and the prospect of tantalizing novel mechanisms to inhibit inflammation in atherosclerosis. However, further studies are required to both dissect the role of endogenous DNA damage and determine whether protection against damage or increased DNA repair are beneficial over and above the standard clinical approach of reducing risk factors for coronary artery disease that promote damage, including hypercholesterolemia, diabetes mellitus, and smoking.…”

“…However, further studies are required to both dissect the role of endogenous DNA damage and determine whether protection against damage or increased DNA repair are beneficial over and above the standard clinical approach of reducing risk factors for coronary artery disease that promote damage, including hypercholesterolemia, diabetes mellitus, and smoking. For example, the experimental system used by by Tumurkhuu et al 11 uses loss of function of both OGG1 and NLRP3 in mice. While they show that atherosclerosis does show loss of macrophage OGG1 expression, rescue experiments overexpressing OGG1 would be required to demonstrate that the reduced OGG1 levels actually present in macrophages in vivo in atherosclerosis have the same functional consequences, and provide proof of principle for macrophage OGG1 being a therapeutic target.…”