Volume 2 • Issue 4 • 1000e118 J Nanomed Biotherapeut Discov ISSN:2155-983X JNBD an open access journal Editorial Open Access Nanomedicine & Biotherapeutic Discovery Krysko, J Nanomed Biotherapeut Discov 2012, 2:4 http://dx.doi.org/10.4172/2155-983X.1000e118 Abbreviations: ATP: Adenosine Triphosphate; CRT: Calreticulin; DAMP: Damage-Associated Molecular Pattern; MYD88; Myeloid Diferentiation Primary Response Gene 88; NLR: he Nucleotide- Binding Oligomerization Domain (NOD)-Like Receptor; PRR: Pattern-Recognition Receptor; RLR: RIG-I-Like Receptor; TLR: Toll- Like Receptor he ‘danger theory’ was irst proposed by Polly Matzinger in 1994. his theory states that the immune system can distinguish self from non-self and dangerous from innocuous signals [1]. his theory has become widely accepted in recent years, especially with the formulation of immunogenic cell death (ICD) concept [2]. Immunogenic characteristics of ICD are mediated mainly by molecules called ‘Damage-Associated Molecular Patterns’ (DAMPs). hese are intracellular molecules normally hidden within live cells, but they acquire immunostimulatory properties upon exposure/release/ secretion by damaged/dying cells. It was recently reported that only certain agents (e.g. anthracyclines, γ-irradiation and hypericin based photodynamic therapy) induce active emission of DAMPs by dying apoptotic cells, and this property determines the eicacy of anti-cancer therapy in the experimental tumor prophylactic vaccination model [3-5]. hese studies have shown that surface exposure of calreticulin (CRT), a soluble protein normally located in the lumen of the endoplasmic reticulum, on tumor cells undergoing ICD in response to certain chemotherapeutics (e.g. anthracyclines) facilities their engulfment by dendritic cells (DCs). his leads to tumor-antigen presentation and tumor-speciic cytotoxic-T lymphocyte (CTL) responses [3]. It is important to stress that the molecular signaling pathways involved in CRT exposure are strongly dependent on the ICD inducer [4,5]. Another DAMP shown to be actively secreted from cells undergoing ICD is ATP [5,6]. Secretion of ATP, which occurs very early during apoptosis, is also tightly regulated by molecular program(s) [5]. Upon their exposure or release by dying cells, DAMPs interact with membrane-bound or vesicular pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), purinergic receptors, NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) [7,8]. For example, it has been shown that extracellular ATP released from cells undergoing ICD activates purinergic P2X7 receptors on DCs. his activates the NALP3–ASC–inlammasome and drives the secretion of IL-1β, which is required for the polarization of interferon-γ (IFN-γ)-producing CD8+ T cells and for the immune response to tumor cells [9]. We also recently demonstrated that the TLR-2/TLR-9-MyD88 signaling pathways have a central role in initiating the acute inlammatory response to cells undergoing ICD [10]. Substantial progress has been made over the past few years in identifying the DAMPs exposed/released/secreted during ICD and the molecular mechanisms of their emission and recognition by the innate and adaptive immune systems. Indeed, nanoparticles and their applications in biomedicine and medicine has become an extensive area of research [11]. It is important to analyze whether nanopartciles act as DAMPs, whether they can be designed with unique immunomodulatory properties (dependent on size, shape, surface charge and solubility), and if they can instigate diferent immunological responses. hese immunomodulatory properties might be speciic for a precise physical type of engineered nanoparticle, and further studies are required to identify and analyze nanoparticle-associated molecular patterns (NAMPs) [12]. Since nanoparticles are also designed to target tumors in vivo and are intended for use as therapeutic drug carriers [11], it will be important to analyze whether drugs delivered in nanoparticles will have increased (or changed) immunogenic potential in terms of induction of ICD and emission of DAMPs. Acknowledgments I thank Dr A Bredan for editing the manuscript. This work was supported by project grants from the Fund for Scientiic Research Flanders (FWO-Vlaanderen, G.0728.10 and 3G067512 to DVK). DVK is a senior postdoctoral fellow paid by fellowship from FWO-Vlaanderen. References 1. Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12: 991-1045. 2. Zitvogel L, Kepp O, Kroemer G (2010) Decoding cell death signals in inlammation and immunity. Cell 140: 798-804. 3. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, et al. (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 13: 54-61. 4. Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, et al. (2009) Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J 28: 578-590. 5. Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, et al. (2012) A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J 31: 1062-1079. 6. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, et al. (2011) Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334: 1573-1577. 7. Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, et al. (2010) Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim Biophys Acta 1805: 53-71. 8. Krysko DV, Agostinis P, Krysko O, Garg AD, Bachert C, et al. (2011) Emerging role of damage-associated molecular patterns derived from mitochondria in inlammation. Trends Immunol 32: 157-164. 9. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, et al. (2009) Activation of the NLRP3 inlammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15: 1170-1178. *Corresponding author: Dmitri V Krysko, Ph.D, Department for Molecular Biomedical Research, VIB-Ghent University, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium, Europe, Tel: 32 9 3313723; Fax: +32 9 3313609; E-mail: Dmitri.Krysko@dmbr.ugent.be Received July 03, 2012; Accepted July 04, 2012; Published July 06, 2012 Citation: Krysko DV (2012) Immunogenic Cell Death and Emission of Damps: Calreticulin and ATP. J Nanomed Biotherapeut Discov 2:e118. doi:10.4172/2155- 983X.1000e118 Copyright: © 2012 Krysko DV. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Immunogenic Cell Death and Emission of Damps: Calreticulin and ATP Dmitri V Krysko 1,2 * 1 Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, Ghent, Belgium 2 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium