Abstract 14850: Independent Role of the Priming and Triggering of the NLRP3 Inflammasome in the Heart
Introduction: The NLRP3 inflammasome is activated in the heart following ischemic injury, and it promotes cardiac dysfunction. Ischemic injury establishes both a priming signal (leading to transcription of inflammasome components) and a trigger (NLRP3 activation). Whether activation of NLRP3 (in absence of priming) represents the limiting step in the formation of the inflammasome in the heart is unknown.
Hypothesis: Both priming and the triggering signals in the heart are necessary for the formation of the inflammasome and ensuing cardiac dysfunction.
Methods: We induced systemic expression of a floxed mutant NLRP3-A350V, that is constitutively active, in 10 mice using a tamoxifen-inducible Cre recombinase, to create a condition in which NLRP3 is activated, in absence or presence of priming with low dose LPS (2 mg/kg). Molecular analyses were performed on the heart and the spleen (myeloid organ not dependent on priming) to measure caspase-1 activity using a fluorogenic assay, mRNA expression of the component of the inflammasome (caspase-1 and IL-1β), and echocardiography to measure left ventricular (LV) dimension and systolic function.
Results: NLRP3-A350V mutant mice had increased caspase-1 activity in the spleen but not in the heart and had normal LV systolic function (Figure), showing that in NLRP3 activation without priming is insufficient to induce inflammasome formation in the heart nor LV systolic dysfunction. Priming with LPS induced the expression of the inflammasome components in the heart which in absence of NLRP3 activation (control mouse) had no effects on LV systolic function, whereas in the presence of NLRP3 activation (mutant mouse) led to reduced LV systolic function and premature death (Figure).
Conclusions: The inflammasome formation in the heart requires a priming signal to be coupled with activation of NLRP3 in order to induce LV dysfunction.
Author Disclosures: S. Toldo: None. E. Mezzaroma: None. M.D. McGeough: None. C.A. Pena: None. C. Marchetti: None. C. Sonnino: None. B.W. Van Tassell: None. A.G. Mauro: None. F.N. Salloum: None. H.M. Hoffman: None. A. Abbate: Research Grant; Modest; Grifols. Other Research Support; Modest; Swedish Orphan Biovitrum. Research Grant; Significant; Novartis.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.