Abstract 11922: Adiponectin Limits Monocytic Microparticle-Induced Inflammasome Activation and Endothelial Dysfunction
Introduction: Monocytic microparticles (mono-MPs) play a fundamental role in the atherothrombotic process. Alterations in monocyte-endothelial cell (EC) interaction mediate immune activation and propagate inflammation. Adiponectin primes monocyte differentiation into anti-inflammatory M2 vs. pro-inflammatory M1 macrophages and inhibits EC activation.
Hypothesis: We hypothesized that mono-MPs trigger NLRP3 inflammasome-dependent EC activation and adiponectin inhibits this phenomenon, in part, through limiting mono-MP production and activation.
Methods: Mono-MPs were characterized using electron microscopy, flow cytometry and NanoSight microscopy. Exosomes were excluded based on size and absence of the exosome-specific markers. Studies were conducted with THP-1 monocytes and peritoneal monocytes from adiponectin knockout (Adipoq-/-) mice. We evaluated the effects of lipopolysaccharide (LPS; 5 μg/ml, 24 h) and recombinant adiponectin (10 μg/ml) on mono-MP production, expression of the NLRP3 inflammasome and its components, and key downstream inflammatory factors. We also studied how MPs alter the expression of critical adhesion molecules and inflammatory transcription factors in HUVEC cultures. Inflammasome activation was examined in mono-MPs derived from THP-1 cells.
Results: Adiponectin suppressed LPS-induced MP generation by THP-1 monocytes. LPS-treated mono-MPs exhibited a marked upregulation in NLRP3 inflammasomes and NLRP3 components (ASC, caspase-1, pro-IL1β and IL1β). Adiponectin attenuated these changes. Adiponectin inhibited the significant increases in ICAM-1, VCAM-1, p-IkB, p-NFkB and p-ERK-1 noted in mono-MP-HUVEC co-cultures. Compared to monocytes from Adipoq+/+ mice, those from Adipoq-/- littermates showed a ~6-fold greater production of MPs following LPS stimulation.
Conclusions: We report a novel mechanism through which mono-MPs sustain NLRP3 inflammasome activation and endothelial dysfunction. These data reveal a previously unknown atheroprotective mechanism for adiponectin that may account for the inverse relationship between circulating adiponectin levels and the risk of diabetes and obesity.
Author Disclosures: M. Ehsan: None. F. Lovren: None. A. Quan: None. Y. Pan: None. K.K. Singh: None. H. Teoh: None. S. Verma: None.
- © 2014 by American Heart Association, Inc.