NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling

Abstract

The NLRP3-IL-1β pathway plays an important role in adipose tissue (AT)-induced inflammation and the development of obesityassociated comorbidities. We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix (ECM) remodeling. Samples obtained from 98 subjects were used in a case−control study. The expression of different components of the inflammasome as well as their main effectors and inflammation-and ECM remodeling-related genes were analyzed. The impact of blocking NLRP3 using siRNA in lipopolysaccharide (LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated. We demonstrated that obesity (P < 0.01), obesity-associated T2D (P < 0.01) and NAFLD (P < 0.05) increased the expression of different components of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT. We also found that obese patients with T2D exhibited increased (P < 0.05) hepatic gene expression levels of NLRP3, IL1B and IL18. We showed that NLRP3, but not NLRP1, is regulated by inflammation and hypoxia in visceral adipocytes. We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked (P < 0.01) LPS-induced inflammation by downregulating the mRNA levels of CCL2, IL1B, IL6, IL8, S100A8, S100A9, TLR4 and TNF as well as inhibiting (P < 0.01) the secretion of IL1-β into the culture medium. Furthermore, blocking NLRP3 attenuated (P < 0.01) the LPS-induced expression of important molecules involved in AT fibrosis (COL1A1, COL4A3, COL6A3 and MMP2). These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.

Increased inflammasome activity in subcutaneous adipose tissue of patients with metabolic syndrome

“…We show that caspase1 positively correlated with SAT IL‐1β while IL‐18 correlation was not‐significant with a trend ( P = .08). This non‐significant correlation with IL‐18 suggest that induction of IL‐18 in SAT is not only dependent on NLRP3 inflammasome activation but may be also driven by NLRP1 inflammasome which mainly induces the production of IL‐18 in adipose tissue 21,39 . We also observe that caspase1 correlate positively with key cardio‐metabolic features.…”

“…The innate immune cell sensor, NLRP3 inflammasome, has been implicated in the pathogenesis of obesity‐induced inflammation and insulin resistance through the activation of caspase‐1, and subsequent release of the cytokines interleukin (IL)‐1β and IL‐18 16‐18 . There is convincing data from published studies of increased inflammation and NLRP3 inflammasome activity in human obesity and diabetes corroborating the data in animal models 16‐23 . However with respect to human MetS there appears to be a paucity of data on the activity of the NLRP3 Inflammasome 24 .…”

Lipids, inflammasomes, metabolism, and disease

“…193 Finally, inhibition of NLRP3 in human visceral adipocytes attenuated adipose tissue fibrosis. 194 These studies propose that caspase-1 activation and IL-1β production affect multiple facets of adipocytes.…”

Does C-C Motif Chemokine Ligand 2 (CCL2) Link Obesity to a Pro-Inflammatory State?

“…Proteoglycans immobilize CCL2 and present it to macrophages resulting in higher AT inflammation [ 140 , 141 , 142 ] ( Figure 3 ). Inhibition of NLRP3 and subsequent reduction of AT CCL2 expression has been shown to reduce fibrosis and related AT inflammation [ 143 ]. In addition to monocyte recruitment into AT, the CCL2-CCR2 axis has been identified as an important mechanism of how AT inflammation in visceral depots may recruit regulatory T cells in a sex hormone-dependent manner [ 144 ].…”