AIM2 Deficiency Alleviates Cardiac Inflammation and Hypertrophy in HFD/STZ-Induced Diabetic Mice by Inhibiting the NLRC4/IRF1 Signaling Pathway.

Abstract

Absent in melanoma 2(AIM2) exacerbates atherosclerosis by inflammasome assembly. However, AIM2-mediated inflammation in diabetic cardiomyopathy remains incompletely understood. Here we investigate the role of AIM2 in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. By RNA-seq, we found that AIM2 were significantly upregulated in HG-induced macrophages, upregulation of AIM2 in cardiac infiltrating macrophages was confirmed in a high-fat diet (HFD)/streptozotocin (STZ)-induceddiabetic mouse model . Therefore, AIM2 knockout mice were constructed. Compared to WT mice, HFD/STZ-induced cardiac hypertrophy and dysfunction were significantly improved in AIM2^-/- mice, despite no changes in blood glucose and body weight. Further, AIM2 deficiency inhibited cardiac recruitment of M1-macrophages and cytokine production. Mechanistically, AIM2-deficient macrophgaes reduced IL-1β and TNF-α secretion, which impaired the NLRC4/IRF1 signaling in cardiomyocytes, and reduced further recruitment of macrophages, attenuated cardiac inflammation and hypertrophy, these effects were confirmed by silencing IRF1 in WT mice, and significantly reversed by overexpression of IRF1 in AIM2^-/- mice. Taken together, our findings suggest that AIM2 serves as a novel target for the treatment of diabetic cardiomyopathy.