e63 Correspondence We welcomed the correspondence by Dr Takahashi regarding the functions of NLRP3. In our article, 1 we had focused on interleukin-1, and, as such, we mainly discussed the inflammasome-dependent NLRP3 functions, but we fully agree with the concept that NLRP3 has inflammasome-independent functions. How important the inflammasome-independent functions of NLRP3 are in heart disease is unclear. To summarize, the NLRP3 is one of the sensors involved in the macromolecular assembly that leads to caspase-1 activation and the maturation of pro–interleukin-1β, the inflammasome. As such, the inflammasome can form in absence of NLRP3 when another sensor is activated. When activated, NLRP3 recruits the adaptor protein ASC, which is the main scaffold protein of the inflammasome. Activation of the inflammasome leads to caspase-1–dependent cell death known as pyroptosis or pyronecrosis. 2 A study in leukocytes carrying a mutant form of constitutively active NLRP3 showed that the induction of cell death could not be rescued by caspase-1 inhibition, yet it was dependent on the presence of ASC, demonstrating that NLRP3/ASC can be involved in modalities of cell death independent of caspase-1. 3 Moreover, studies in genetically modified mice lacking NLRP3 or ASC showed that NLRP3 can promote cell death also independent of ASC, 4 a form of cell death independent of caspase-1 that appears to have morphological characteristics common to oncosis and apop- tosis. Caspase-1–dependent cell death, however, appears to be very important in experimental acute myocardial infarction and heart fail- ure, 2,5,6 and whether NLRP3-mediated/caspase-1-independent cell death contributes to the injury or not needs to be further investigated. Disclosures Dr Abbate has received research grants from AB2 Bio, Gilead, Novartis, and XOMA; has lectured for Glaxo-Smith-Kline, Novartis, and XOMA; and has consulted for Gilead, Janssen, Omni Biopharma, Swedish Orphan Biovitrum, and XOMA. Dr Van Tassell has received research grants from Gilead and Novartis and has consulted for Novartis. The other authors report no conflicts. Benjamin W. Van Tassell, PharmD School of Pharmacy Victoria Johnson Research Center Virginia Commonwealth University Richmond, VA Stefano Toldo, PhD Victoria Johnson Research Center VCU Pauley Heart Center Virginia Commonwealth University Richmond, VA Eleonora Mezzaroma, PhD School of Pharmacy Victoria Johnson Research Center Virginia Commonwealth University Richmond, VA Antonio Abbate, MD Victoria Johnson Research Center VCU Pauley Heart Center Virginia Commonwealth University Richmond, VA References 1. Van Tassell BW, Toldo S, Mezzaroma E, Abbate A. Targeting interleu- kin-1 in heart disease. Circulation. 2013;128:1910–1923. 2. Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FN, Kannan HR, Menna AC, Voelkel NF, Abbate A. The inflamma- some promotes adverse cardiac remodeling following acute myo- cardial infarction in the mouse. Proc Natl Acad Sci U S A. 2011;108: 19725–19730. 3. Satoh T, Kambe N, Matsue H. NLRP3 activation induces ASC-dependent programmed necrotic cell death, which leads to neutrophilic inflamma- tion. Cell Death Dis. 2013;4:e644. 4. Inoue Y, Shirasuna K, Kimura H, Usui F, Kawashima A, Karasawa T, Tago K, Dezaki K, Nishimura S, Sagara J, Noda T, Iwakura Y, Tsutsui H, Taniguchi S, Yanagisawa K, Yada T, Yasuda Y, Takahashi M. NLRP3 regulates neutrophil functions and contributes to hepatic ischemia- reperfusion injury independently of inflammasomes. J Immunol. 2014;192:4342–4351. 5. Syed FM, Hahn HS, Odley A, Guo Y, Vallejo JG, Lynch RA, Mann DL, Bolli R, Dorn GW 2nd. Proapoptotic effects of caspase-1/inter- leukin-converting enzyme dominate in myocardial ischemia. Circ Res. 2005;96:1103–1109. 6. Marchetti C, Chojnacki J, Toldo S, Mezzaroma E, Tranchida N, Rose SW, Federici M, Van Tassell BW, Zhang S, Abbate A. A novel pharma- cologic inhibitor of the NLRP3 inflammasome limits myocardial injury following ischemia-reperfusion in the mouse. J Cardiovasc Pharmacol. 2014;63:316–322. (Circulation. 2014;130:e63.) © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.114.010274 Response to Letter Regarding Article, “Targeting Interleukin-1 in Heart Disease” by guest on May 30, 2016 http://circ.ahajournals.org/ Downloaded from