TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation

Krysko, Dmitri V.; Kaczmarek, Agnieszka; Krysko, Olga; Heyndrickx, Liesbeth; Woznicki, Jerzy; Bogaert, Pieter; Cauwels, Anje; Takahashi, Nozomi; Magez, Stefan; Bachert, Claus; Vandenabeele, Peter

doi:10.1038/cdd.2011.4

Cited by 107 publications

(76 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Anti-inflammation treatments not only suppressed doxorubicin-caused myocardial inflammation but also prevented cardiaomyopathy (7)(8)(9). Previous studies suggested that the systemic inflammation was stimulated by tissue damage or cell apoptosis due to the toxicity of this drug (26). However, inflammatory responses triggered by tissue damage should be transient and self-restricted.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

et al. 2016

View full text Add to dashboard Cite

Doxorubicin is one of the most effective chemotherapeutic agents used for cancer treatment, but it causes systemic inflammation and serious multiorgan side effects in many patients. In this study, we report that upregulation of the proinflammatory Toll-like receptor TLR4 in macrophages by doxorubicin is an important step in generating its toxic side effects. In patient serum, doxorubicin treatment resulted in leakage of endotoxin and inflammatory cytokines into circulation. In mice, doxorubicin damaged the intestinal epithelium, which also resulted in leakage of endotoxin from the gut flora into circulation. Concurrently, doxorubicin increased TLR4 expression in macrophages both in vitro and in vivo, which further enhanced the sensitivity of these cells to endotoxin. Either depletion of gut microorganisms or blockage of TLR4 signaling effectively decreased doxorubicininduced toxicity. Taken together, our findings suggest that doxorubicin-triggered leakage of endotoxin into the circulation, in tandem with enhanced TLR4 signaling, is a candidate mechanism underlying doxorubicin-induced systemic inflammation. Our study provides new insights for devising relevant strategies to minimize the adverse effects of chemotherapeutic agents such as doxorubicin, which may extend its clinical uses to eradicate cancer cells. Cancer Res; 76(22); 6631-42. Ó2016 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

et al. 2016

View full text Add to dashboard Cite

show abstract

“…2 Mechanistically, the immunogenic apoptotic bodies induced by exposure to doxorubicin are sensed by APCs through their TLR-2/TLR-9-MyD88 signaling pathways. 17 …”

Section: Apoptotic Cell Death As Icdmentioning

confidence: 99%

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

2013

View full text Add to dashboard Cite

Apoptotic cell death generally characterized by a morphologically homogenous entity has been considered to be essentially non-immunogenic. However, apoptotic cancer cell death, also known as type 1 programmed cell death (PCD), was recently found to be immunogenic after treatment with several chemotherapeutic agents and oncolytic viruses through the emission of various danger-associated molecular patterns (DAMPs). Extensive studies have revealed that two different types of immunogenic cell death (ICD) inducers, recently classified by their distinct actions in endoplasmic reticulum (ER) stress, can reinitiate immune responses suppressed by the tumor microenvironment. Indeed, recent clinical studies have shown that several immunotherapeutic modalities including therapeutic cancer vaccines and oncolytic viruses, but not conventional chemotherapies, culminate in beneficial outcomes, probably because of their different mechanisms of ICD induction. Furthermore, interests in PCD of cancer cells have shifted from its classical form to novel forms involving autophagic cell death (ACD), programmed necrotic cell death (necroptosis), and pyroptosis, some of which entail immunogenicity after anticancer treatments. In this review, we provide a brief outline of the well-characterized DAMPs such as calreticulin (CRT) exposure, high-mobility group protein B1 (HMGB1), and adenosine triphosphate (ATP) release, which are induced by the morphologically distinct types of cell death. In the latter part, our review focuses on how emerging oncolytic viruses induce different forms of cell death and the combinations of oncolytic virotherapies with further immunomodulation by cyclophosphamide and other immunotherapeutic modalities foster dendritic cell (DC)-mediated induction of antitumor immunity. Accordingly, it is increasingly important to fully understand how and which ICD inducers cause multimodal ICD, which should aid the design of reasonably multifaceted anticancer modalities to maximize ICD-triggered antitumor immunity and eliminate residual or metastasized tumors while sparing autoimmune diseases.

show abstract

“…Recent evidence indicates that doxorubicin is able to induce immunogenic cell death (ICD) both in vitro (24) and in vivo (25,26), an effect mainly mediated by damage-associated molecular patterns (DAMP), including cell surface-exposed calreticulin (CRT), secreted ATP, and released high mobility group box 1 protein (HMGB1; ref. 27).…”

Section: Doxorubicin Enhances Lcl Immunogenicitymentioning

confidence: 99%

“…To verify whether the enhanced HMGB1 release showed by DX-LCLs could trigger receptordependent responses in an autocrine/paracrine fashion, we evaluated the expression of its functional receptor, TLR4, and of its downstream adaptor molecule Myeloid Differentiation primary response 88 (MyD88; ref. 26). Flow cytometry analysis showed that doxorubicin and cisplatin markedly increased the number of TLR4-expressing cells (63.3% and 54.4%, respectively) compared with control LCLs (38.1% of positive cells), whereas TPA þ NaB Ã 02 (top) and TLR4 (bottom) was analyzed by flow cytometry at t24, whereas CRT expression (center) was investigated after 3 hours.…”

Section: Doxorubicin Enhances Lcl Immunogenicitymentioning

confidence: 99%

Broadening Specificity and Enhancing Cytotoxicity of Adoptive T Cells for Nasopharyngeal Carcinoma Immunotherapy

Faè

Martorelli

Mastorci

et al. 2016

Cancer Immunology Research

View full text Add to dashboard Cite

Although promising, clinical responses to adoptive immunotherapy for nasopharyngeal carcinoma (NPC) are still limited by the restricted number of Epstein-Barr virus (EBV) antigens that can be targeted and their poor immunogenicity. Our previous work indicated that the immunogenic features of the NPCassociated viral antigen BARF1 may be exploited for immunotherapeutic purposes. Nevertheless, T-cell lines obtained with current protocols include only negligible numbers of BARF1-specific cytotoxic T lymphocytes, pointing to the need to enrich these effectors in BARF1 specificities. Considering that in B lymphocytes BARF1 is mainly a lytic EBV antigen, we tested different EBV lytic-cycle inducers (TPA/butyric acid, doxorubicin, and cisplatin) used at suboptimal concentrations for their ability to upregulate BARF1 expression in lymphoblastoid B-cell lines (LCL), the commonly used antigen-presenting cells, without compromising their survival. The LCLs treated with doxorubicin (DX-LCL) can reproducibly and efficiently generate EBV-specific effectors enriched in BARF1 specificities from both healthy donors and NPC patients. These DX-LCLs also had more pronounced immunogenic properties, including HLA class I upregulation and expression of immunogenic cell death markers, such as enhanced calreticulin exposure and HMGB1 release. In particular, doxorubicin triggers an HMGB1 autocrine/ paracrine loop with its receptor, TLR4, which is also upregulated in DX-LCLs and is responsible for NF-kB activation and a delayed apoptosis that allows a prolonged stimulation of EBV-specific T-cell precursors. This protocol may thus constitute a valid alternative to the use of engineered LCLs to generate EBV-specific T-cell lines for adoptive immunotherapy, being relatively simple, easily upgradable to Good Manufacturing Practice standards, and therefore more broadly applicable.

show abstract

TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation

Cited by 107 publications

References 39 publications

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

Broadening Specificity and Enhancing Cytotoxicity of Adoptive T Cells for Nasopharyngeal Carcinoma Immunotherapy

Contact Info

Product

Resources

About