Introduction: the immune response against dying cells

Zitvogel, Laurence; Kroemer, Guido

doi:10.1016/j.coi.2008.07.009

Cited by 12 publications

(6 citation statements)

References 14 publications

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“…101 In the arterial intima, immature DCs can be activated by various stimuli. [101][102][103][104][105][106] Cellular components, released from dying cells, collectively called damage-associated molecular patterns and pathogen-associated molecular patterns that originate from microbes and viruses can induce the activation and maturation of DCs. [7][8][9] Ultrastructural analysis of the nondiseased intima of athero-prone areas of the aorta has shown that in this location, there is a casual presence of dying cells and cells exhibiting signs of destruction.…”

Section: Tissue Microenvironment In Atherosclerosis and DC Functionmentioning

confidence: 99%

Dendritic cells and their role in atherogenesis

Bobryshev

2010

Laboratory Investigation

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Dendritic cells (DCs) are the most potent professional antigen-presenting cells with the unique ability of primary immune response initiation. DCs originate from bone marrow progenitors, which circulate in the peripheral blood and subsequently penetrate peripheral tissues, where they give rise to immature DCs. In peripheral tissues, DCs continuously monitor the microenvironment and, when the cells encounter 'danger' signals, DCs undergo differentiation and maturation. Maturing DCs usually migrate to lymphatic tissues, where they form contacts with T cells to initiate a primary immune response. DCs were identified in arteries in 1995 and since then, further knowledge has been gained about the peculiarities of vascular-associated DCs and their role in atherosclerosis. Immune reactions toward modified lipoproteins and other factors ignited by resident vascular DCs as well as by newly arrived DCs, which originate from blood monocytes, are believed to destabilize arterial homeostasis from very earlier stages of atherogenesis. There is a remarkable heterogeneity of DCs in atherosclerotic lesions. Some DCs mature and become capable of forming clusters with T cells directly within the arterial wall. The predictive value of the numbers of circulating DC precursors in coronary artery disease and in atherosclerosis has been assessed, and it has been shown that DCs have a role in plaque destabilization. Over recent decades, DCs have proven to be a valuable instrument in immunotherapy approaches against cancer and various autoimmune diseases, and this explains the demand that the accumulated knowledge be applied to the field of atherosclerosis immunotherapy.

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Section: Tissue Microenvironment In Atherosclerosis and DC Functionmentioning

confidence: 99%

Dendritic cells and their role in atherogenesis

Bobryshev

2010

Laboratory Investigation

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“…7 One of the major challenges of the immune system is hence to discriminate between normal developmental or homeostatic cell death, on one side, and virus-induced pathological cell death, on the other side. [8][9][10] To avoid devastating autoimmune reactions, physiological cell death should not induce any kind of immune response other than self-tolerizing reactions. In sharp contrast, pathogen-induced cell death should stimulate vigorous innate and cognate immune responses, with the dual aim to eliminate virusinfected cells and to induce a long-term protective immune memory that avoids re-infection by the same microorganism.…”

Section: Introductionmentioning

confidence: 99%

Viral subversion of immunogenic cell death

et al. 2009

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While physiological cell death is non-immunogenic, pathogen induced cell death can be immunogenic and hence stimulate an immune response against antigens that derive from dying cells and are presented by dendritic cells (DCs). The obligate immunogenic "eat-me" signal generated by dying cells consists in the exposure of calreticulin (CRT) at the cell surface. This particular "eat-me" signal, which facilitates engulfment by DCs, can only be found on cells that succumb to immunogenic apoptosis, while it is not present on cells dying in an immunologically silent fashion. CRT normally resides in the lumen of the endoplasmic reticulum (ER), yet can translocate to the plasma membrane surface through a complex pathway that involves elements of the ER stress response (e.g., the eIF2α-phosphorylating kinase PERK), the apoptotic machinery (e.g., caspase-8 and its substrate BAP31, Bax, Bak), the anterograde transport from the ER to the Golgi apparatus, and SNARE-dependent exocytosis. A large panoply of viruses encodes proteins that inhibit eIF2α kinases, catalyze the dephosphorylation of eIF2α, bind to caspase-8, Bap31, Bax or Bak, or perturb exocytosis. We therefore postulate that obligate intracellular pathogens have developed a variety of strategies to subvert CRT exposure, thereby avoiding immunogenic cell death.

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“…45 A role for CCL2 in early stages of tumour development was also suggested in the study by Granot et al , 43, 45, 46, 47 which suggested that CCL2 expression levels may be critical in maintaining an anti-tumour environment, but that the tumour cells may, under certain circumstances, outcompete the cytotoxic effects of immune cells, escaping anti-tumour responses, resulting in clinically detectable tumours and/or disease with poorer outcomes. This may explain why the xenografts derived from OV-90 and the CCL2 -expressing clones appeared indistinguishable when they were collected from the mice at killing.…”

Section: Discussionmentioning

confidence: 87%

Overexpressing the CCL2 chemokine in an epithelial ovarian cancer cell line results in latency of in vivo tumourigenicity

et al. 2012

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The frequent loss of heterozygosity of chromosome (Chr) 17 in epithelial ovarian cancer (EOC), particularly high-grade ovarian serous carcinomas (HGOSCs), has been attributed to the disruption of known tumour suppressor genes, such as TP53 (17p13), as well as other genes on this chromosome that alone or in combination have a role in EOC. In a transcriptome analysis of Chr17 genes, we observed significant underexpression of the chemokine CCL2 (17q12) in a small set of HGOSC samples relative to normal ovarian surface epithelial cells and a significant upregulation of CCL2 in the TP53-mutated OV-90 EOC cell line rendered non-tumourigenic as a consequence of genetic manipulation. Here, we report that overexpressing CCL2 in OV-90 resulted in latency of tumour formation at intraperitoneal (i.p.) but not subcutaneous sites in a mouse xenograft model. Overexpressing CCL2 affected cell morphology and exerted modest, but not significant effects on cell viability, colony formation and cell migration. We report significant underexpression of CCL2 by transcriptome analysis (P=0.015) and by immunohistochemistry in 77% of HGOSC samples (n=65). Absent or a very low level of protein expression by immunohistochemistry was also observed in 71% of additional HGOSC samples (n=122). However, CCL2 protein expression did not significantly correlate with overall or disease-free survival. The epithelial cells of normal fallopian tubes, a purported origin of HGOSC, exhibited expression of CCL2 protein by immunohistochemistry. Our results affirm that CCL2 underexpression is a significant feature of HGOSC samples, and that CCL2 overexpression in an EOC cell line model affects tumourigenic potential in the i.p. setting.

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Introduction: the immune response against dying cells

Cited by 12 publications

References 14 publications

Dendritic cells and their role in atherogenesis

Dendritic cells and their role in atherogenesis

Viral subversion of immunogenic cell death

Overexpressing the CCL2 chemokine in an epithelial ovarian cancer cell line results in latency of in vivo tumourigenicity

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