AIM2-driven inflammasome activation in heart failure

Abstract

Aims Interleukin-1β (IL-1β) is an important pathogenic factor in cardiovascular diseases including chronic heart failure (HF). The CANTOS trial highlighted that inflammasomes as primary sources of IL-1 β are promising new therapeutic targets in cardiovascular diseases. Therefore, we aimed to assess inflammasome activation in failing hearts to identify activation patterns of inflammasome subtypes as sources of IL-1β. Methods and Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human heart failure regardless of the etiology (ischemic or dilated cardiomyopathy) while the NLRP1/NALP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change in HF samples. AIM2 expression was primarily detected in monocytes/macrophages of failing hearts. Translational animal models of HF (pressure or volume overload, and permanent coronary artery ligation in rat, as well as ischemia/reperfusion-induced HF in pigs) demonstrated activation pattern of AIM2 similar to that of observed in end-stages of human HF. In vitro AIM2 inflammasome activation in human THP-1 monocytic cells and human AC16 cells was significantly reduced by pharmacological blockade of pannexin-1 channels by the clinically used uricosuric drug probenecid. Probenecid was also able to reduce pressure overload-induced mortality and restore indices of disease severity in a rat chronic HF model in vivo. Conclusions This is the first report showing that AIM2 and NLRC4 inflammasome activation contribute to chronic inflammation in heart failure and that probenecid alleviates chronic HF by reducing inflammasome activation. The present translational study suggests the possibility of repositioning of probenecid for HF indications.

The Role of the Inflammasome in Heart Failure

“…AIM2 and NLRC4 expression was also increased in the heart tissue of HF patients and animal models in the late phase of chronic HF induced by pressure-or volume-overload, and following infarction. Activation of the AIM2 inflammasome resulted in activation of both IL-1β and IL-18, and its inhibition with probenecid alleviated chronic HF (Onodi et al, 2021). These findings suggest that AIM2 and NLRC4 are involved in diabetes-related or latephase HF.…”

Analysis of necroptosis and its association with pyroptosis in organ damage in experimental pulmonary arterial hypertension

“…In addition to NLRP3, other main inflammasome sensors, such as NLRC4 and absent in melanoma 2 (AIM2), known to be upregulated in circumstances associated with cardiac injury, 33,34 were also investigated. The expression of NLRC4 was assessed by RT‐qPCR due to similar technical issues as in the case of NLRP3 evaluation.…”

“…Although there is no literary confrontation for such decrease in N‐terminal GSDMD, these data strongly indicate that the RV of subjects with PAH is unlikely affected by pyroptotic cell death. In addition to NLRP3 inflammasome, we also examined whether some other inflammasome sensors associated with chronic cardiac injury 33,34 might underlie RV damage due to PAH. Both NLRC4 and AIM2 levels were upregulated in the RVs of both PAH groups.…”

Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress

“…The NOD-like receptor protein-3 (NLRP3) inflammasome is involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18 [36]. Recent studies implicate connexin (Cx) hemichannels (CxHC) and pannexin-1 channels in the spread of pro-inflammatory purinergic signaling by NLPR3 or NLRC4 inflammasome in the cardiac and vascular systems [17,37]. CxHC's are activated in pathophysiological settings that promote cardiac arrhythmia development, and NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias [38,39].…”

“…While cardiac inflammation can be enhanced by sympathetic overdrive [46], the β1-adrenergic receptor blockers abrogate inflammation [47]. In addition, some authors consider that metabolic inflammation is central to the pathophysiology of heart failure (HF), with preserved ejection fraction [48], while NLRP3 inflammasome activation contributes to chronic inflammation in HF with reduced ejection fraction [37]. Most recent study provides evidence for genetically driven systemic inflammation in cardiovascular diseases, and it highlights the NLRP3 inflammasome as a therapeutic target [49].…”