HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation

Abstract

Recent studies have demonstrated the stimulatory effects of HMG-CoA reductase inhibitors, statins, on IL-1β secretion in monocytes and suggest a crucial role for isoprenoids in the inhibition of caspase-1 activity. In this study, we further elucidated the molecular mechanisms underlying the stimulatory effects of statins on caspase-1. Three commonly recognized mechanistic models for NLRP3 inflammasome activation (i.e., ATP/P2X7/K(+) efflux, ROS production, and lysosomal rupture) were investigated in statin-stimulated human THP-1 monocytes. We found that fluvastatin and lovastatin can synergize with LPS to trigger inflammasome activation. Moreover, statin-induced caspase-1 activation and IL-1β production in LPS-primed THP-1 cells are dependent on GGPP deficiency and P2X7 activation. In particular, increased ATP release accounts for the action of statins in P2X7 activation. We also provide evidence that statin-induced moderate ROS elevation is involved in this event. Moreover, the cathepsin B inhibitor was shown to reduce statin-induced IL-1β secretion. Consistently statins can induce cathepsin B activation and lysosomal rupture, as evidenced by LysoTracker staining. Statins also increase intracellular ATP secretion and IL-1β release in primary human monocytes and murine macrophages. Notably, exogenous ATP-elicited P2X7 activation and consequent IL-1β release, an index of direct NLRP3 inflammasome activation, were not altered by statins. Taken together, statin-induced enhancement of inflammasome activation in monocytes and macrophages covers multiple mechanisms, including increases in ATP release, ROS production, and lysosomal rupture. These data not only shed new insight into isoprenylation-dependent regulation of caspase-1 but also unmask mechanisms for statin-elicited inflammasome activation.

Fluvastatin Causes NLRP3 Inflammasome-Mediated Adipose Insulin Resistance

“…In contrast, statins have been associated with increased secretion of the proinflammatory cytokine IL-1b; an effect that requires caspase-1 activity and priming with another immunogenic agent such as LPS (4). These features are indicative of regulation by the inflammasome containing the PRR, NOD-like receptor family, pyrin domain containing 3 (NLRP3; also referred to as NACHT, leucine-rich repeat, and pyrin domainscontaining protein 3 or cryopyrin) (5,6). The NLRP3 inflammasome is causally linked to the development of insulin resistance in rodents (7) and has recently been shown to be activated in macrophages of patients with newly diagnosed insulin-resistant type 2 diabetes (8).…”

Is immunity a mechanism contributing to statin-induced diabetes?

“…Statin-mediated inhibition of HMGCR, decreased mevalonate pathway intermediates and reduced protein prenylation may be a critical link, since addition of GGPP to statin-treated culture has been shown to restore ATP levels and inhibit IL-1b release. 17,20,56,59 However, it is not clear which prenylated protein(s) is/are involved. Three distinct prenyltransferases (Farnesyltransferase, FTase; Geranylgeranyltransferase I and II, GGTase-I and GGTase-II) are responsible for prenylation of an array of proteins including Ras, Rho and Rab family proteins.…”

“…[68][69][70][71][72] Statins have also been shown to promote a modest increase in cellular ROS and an increase of ATP release in THP-1 monocytes. 56 Statininduced IL-1b production was also shown to be dependent on P2X purinoceptor 7 (P2X7) activation. Increased extracellular ATP can activate the P2X7 receptor, an ATP-gated ion channel resulting in cellular efflux of K C ions.…”

“…20 Our first finding corresponded with previous research showing statins increase IL-1b secretion in bone marrow derived macrophages (BMDM's) given adequate priming. 56 Statin-induced IL-1b secretion was dependent on NLRP3 and reversed with (a high dose of) the known inflammasome inhibitor, glyburide. 57 We also showed that adding back the mevalonate pathway intermediate GGPP prevented IL-1b release from BMDMs demonstrating a role for prenylated proteins.…”

Are oxidised low-density lipoproteins the true inducers of inflammation in atherosclerosis?

“…Other works suggest that statin-induced inflammasome activation is dependent upon isoprenoid deficiency as well as P2X7 activation. Authors also involve statins in multiple mechanisms, including increasing ATP release, ROS production, and lysosomal rupture [154].…”