Abstract 421: Hematopoietic Deficiency In NLRP3 And AIM2 Inflammasomes Or Gasdermin D Fails To Prevent Atherosclerosis Progression In Mouse Models Of Diabetes

Diabetes accelerates atherosclerosis progression in part by increasing lesional necrotic core expansion, but the underlying mechanisms remain elusive. Previous studies have shown that systemic inhibition of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome prevents atherosclerosis progression in a mouse model of diabetes. Gasdermin D (GSDMD), which acts downstream of inflammasome activation, contributes to pyroptosis and IL-1β and IL-18 release. To explore if hematopoietic inflammasome activation mediates diabetes-related necrotic core expansion, we first generated hematopoietic GSDMD-deficient chimeras in an LDL receptor-deficient ( Ldlr -/- ) virally-induced mouse model of type 1 diabetes (T1D)-accelerated atherosclerosis. Mice with T1D demonstrated elevated plasma glucose, triglycerides, cholesterol, and plasma IL-18 (non-diabetes [ND]=180.4 pg/ml, diabetes [D]=316.6, N=17-18 per group). However, diabetic mice with hematopoietic GSDMD-deficiency had no reduction in plasma IL-18 (D-KO=437.5 pg/ml, p=0.29, N=17). Moreover, we found little evidence of inflammasome activation in peritoneal and splenic macrophages from diabetic mice. A 4-week duration of diabetes significantly increased necrotic core area measured at three different levels in the aortic sinus (p<0.01, N=21-24 per group) in pre-existing lesions without increasing lesion area. Hematopoietic GSDMD-deficiency did not affect the necrotic core area. To further interrogate the relationship between hematopoietic inflammasome activation and diabetes-related necrotic core expansion, we generated Ldlr -/- hematopoietic NLRP3 and absent in melanoma 2 (AIM2) inflammasome double knockout (DKO) chimeras in a streptozotocin mouse model of diabetes. Mice with diabetes demonstrated hyperglycemia and hypercholesterolemia. However, diabetic hematopoietic DKO chimeras did not exhibit reduced aortic sinus necrotic core area, as compared with diabetic wildtype controls. Our findings suggest that the increased plasma IL-18 levels in diabetic mice are not dependent on hematopoietic GSDMD, and that diabetes-mediated necrotic core expansion is independent of hematopoietic NLRP3 and AIM2 inflammasome and pyroptosis pathways.