G Model IMBIO-51301; No. of Pages 1
ARTICLE IN PRESS Immunobiology xxx (2015) xxx–xxx
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Letter to the Editor Effects of dimethyl sulfoxide on the NLRP3 inﬂammasome
inﬂammasome inhibitors, especially when proper DMSO control vehicle are included in the study.
We read with much interest the manuscript by Ahn et al. (2014) on the effects of dimethyl sulfoxide (DMSO) on the NLRP3 inﬂammasome activation. DMSO, given its ability to dissolve hydrophilic and hydrophobic compounds, is a very common solvent and therefore is often used as a vehicle for in vitro and in vivo studies. However, a good amount of data has shown that DMSO is not always inert, both in vitro and in vivo (Xing and Remick, 2005; Julien et al., 2012). In fact, as also disclosed by Ahn et al., DMSO may potentiate the release of IL-1␤ following LPS stimulation (Xing and Remick, 2005). DMSO effects really depend on the model and doses used, but, in the majority of the cases, DMSO is used as a control vehicle for the experimental treatment and shown as proper control to detect the drug effect. Here the authors reported a signiﬁcant inhibitory effect of DMSO on the activity of the NLRP3 inﬂammasome. In particular, it reduced IL-1␤ release following treatment with speciﬁc NLRP3 activators and decreased caspase-1 activity following nigericin stimulation in vitro (Ahn et al., 2014). Furthermore, use of DMSO in vivo, improved survival and reduction in body weight following treatment with LPS and dextran sulfate sodium (DSS) respectively, suggesting a protective effect of DMSO in these models (Ahn et al., 2014). In a recent publication aimed at testing the effects of an NLRP3 inﬂammasome inhibitor in vivo and in vitro (Marchetti et al., 2014), we used DMSO as solvent and we experienced only mild or no effects of the DMSO vehicle on caspase-1 activity from heart tissue or in cardiac damage, measured as serum cardiac troponin I level or infarct size, when compared to the salinetreated mice following acute myocardial infarction (Marchetti et al., 2014). Likewise, in a model of zymosan-induced peritonitis, the intensity of leukocyte inﬁltration in the peritoneal cavity was similar between saline and vehicle-treated group (data not published). In vitro, we have seen that a line of cardiomyocytes, the HL-1 cells, when treated with LPS and nigericin in the presence of 2% DMSO has a signiﬁcant increased in caspase-1 activity compared to the untreated cells, while in the manuscript by Ahn et al., the authors found an inhibitory effect of DMSO in cells. We are aware that the differences in experimental models, doses and time of treatment may make difﬁcult to compare data between different publications and it represents an important limitations. However, when compared to vehicle without DMSO, our results did not suggest a direct effect of DMSO in decreasing the NLRP3 inﬂammasome activity. We believe that DMSO is still a good solvent for drugs used as
Conﬂict of interest None of the authors have any conﬂicts of interest to disclose. References Ahn, H., Kim, J., Jeung, E.B., Lee, G.S., 2014. Dimethyl sulfoxide inhibits NLRP3 inﬂammasome activation. Immunobiology 219, 315–322. Julien, C., Marcouiller, F., Bretteville, A., El Khoury, N.B., Baillargeon, J., Hebert, S.S., Planel, E., 2012. Dimethyl sulfoxide induces both direct and indirect tau hyperphosphorylation. PLoS ONE 7, e40020. Marchetti, C., Chojnacki, J., Toldo, S., Mezzaroma, E., Tranchida, N., Rose, S.W., Federici, M., Van Tassell, B.W., Zhang, S., Abbate, A., 2014. A novel pharmacologic inhibitor of the NLRP3 inﬂammasome limits myocardial injury after ischemiareperfusion in the mouse. J. Cardiovasc. Pharmacol. 63, 316–322. Xing, L., Remick, D.G., 2005. Mechanisms of dimethyl sulfoxide augmentation of IL-1 beta production. J. Immunol. 174, 6195–6202.
Carlo Marchetti a,b VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA b Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, VA, USA b
Eleonora Mezzaroma b,c Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, VA, USA c School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
Stefano Toldo a,b,∗ VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA b Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, VA, USA ∗ Corresponding author at: Virginia Commonwealth University, VCU Pauley Heart Center, Box 980281, 1200 East Broad Street, Richmond, VA 23298, USA. E-mail address: [email protected]
8 December 2014 Available online xxx
http://dx.doi.org/10.1016/j.imbio.2015.02.003 0171-2985/© 2015 Elsevier GmbH. All rights reserved.
Please cite this article in press as: Marchetti, C., et al., Effects of dimethyl sulfoxide on the NLRP3 inﬂammasome. Immunobiology (2015), http://dx.doi.org/10.1016/j.imbio.2015.02.003