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Objective: Cell death normally occurs during pregnancy and is critical during its common complication, preeclampsia. The long pentraxin 3 (PTX3) gene is generated in tissues that cope with excessive or deregulated cell death and inhibits the cross-presentation of cell-associated antigens. We examined whether PTX3 is expressed during pregnancy and possibly involved in the development of preeclampsia., Methods: Women with preeclampsia (n = 30), women with uncomplicated pregnancies (n = 66), age-matched healthy women (n = 50), women who developed acute bacterial infections (n = 20), and women with rheumatoid arthritis (n = 20) were studied. The concentrations of PTX3 were measured in the blood by a sandwich enzyme-linked immunosorbent assay (ELISA) and in placentas by immunohistochemistry. The concentrations of PTX3 and C-reactive protein in the various groups were compared by nonparametric tests (the Mann-Whitney U and the Kruskal-Wallis tests). The odds of developing preeclampsia were assessed using logistic regression., Results: PTX3 was expressed in amniotic epithelium and chorionic mesoderm, trophoblast terminal villi, and perivascular stroma in placentas from pregnancies of uncomplicated subjects. Circulating levels steadily rose during normal gestation and peaked during labor. Serum levels of PTX3 were strikingly higher in preeclampsia compared with normal control pregnancies (5.08 +/- 1.34 and 0.59 +/- 0.07 ng/mL, respectively, P < .001). Sites of higher expression in the placentas from preeclamptic patients include infarcts and fibrinoid zones., Conclusion: Defects in the homeostatic response to cell death/remodeling events, revealed by enhanced levels of PTX3, could be implicated in preeclampsia., Level of Evidence: II-2.

Pentraxins (PTX) and complement belong to the humoral arm of the innate immune system and have essential functions in immune defense to microbes and in scavenging cellular debris. The prototypic long PTX, PTX3, and the first component of the classical complement pathway, C1q, are innate opsonins involved in the disposal of dying cells by phagocytes. Whether the interaction between various innate opsonins impacts on their function is not fully understood. We show here that characterized Toll-like receptor (TLR) ligands elicit the production of C1q and PTX3 by immature dendritic cells (DC). Moreover, these molecules bind to dying cells with similar kinetics, although they recognize different domains on the cell membranes. PTX3 binds in the fluid phase to C1q, decreasing C1q deposition and subsequent complement activation on apoptotic cells. C1q increases the phagocytosis of apoptotic cells by DC and the release of interleukin-12 in the presence of TLR4 ligands and apoptotic cells; PTX3 inhibits both events. Moreover, PTX3 inhibited the cross-presentation of the MELAN-A/melanoma antigen-reactive T cell 1 (MART-1) tumor antigen expressed by dying cells, even in the presence of C1q. These results suggest that interaction of C1q and PTX3 influences the clearance of apoptotic cells by DC. The coordinated induction by primary, proinflammatory signals of C1q and PTX3 and their reciprocal regulation during inflammation influences the clearance of apoptotic cells by antigen-presenting cells and possibly plays a role in immune homeostasis.

Tumor necrosis factor-alpha (TNFalpha) is a main actor in the pathogenesis of rheumatoid arthritis (RA), interacting with other molecules in complex mechanisms. The neuroendocrine system is known to be involved and Chromogranin A (CHGA) serum levels are elevated in patients with RA. We evaluated the effect of the selective blockade of TNF-alpha, induced by treatment with anti-TNF-alpha monoclonal antibodies (mAbs), on the serum levels of CHGA and on its correlation with TNF-alpha and TNF-alpha receptors (TNFRs) serum levels. Seven patients with RA have been treated with the anti-TNF-alpha mAb, infliximab. We measured the serum levels of TNF-alpha, its receptors (tumor necrosis factor receptor-I [TNFR-I] and tumor necrosis factor receptor-II [TNFR-II]), and CHGA before and during the treatment. We also measured, as a control, the serum levels of CHGA, TNF-alpha, and soluble TNFRs in 14 patients who were being treated with infliximab, adalimumab, or etanercept and in 20 matching negative controls. The serum levels of TNFR-I and TNFR-II, which are a sensitive marker for the TNF-alpha pathway, correlated with those of CHGA before treatment (Pearson's coefficient, respectively, 0.59 and 0.53). Treatment with anti-TNF-alpha mAb provided a significant clinical response in all patients and the correlation between CHGA and TNFR-I and TNFR-II was no more evident during treatment (respectively, -0.09 and -0.07). TNF-alpha blockade allows a clinical effect in patients with RA and modifies the correlation between CHGA and TNFRs, suggesting that TNF-alpha and CHGA reciprocally interfere in the pathogenesis of RA, through intermediate adaptors, whose identification warrants further studies.

Pentraxins are soluble pattern recognition receptors with a dual role: protection against extracellular microbes and autoimmunity. The mechanisms by which they accomplish these tasks are not yet fully understood. Here we show that the prototypic long pentraxin PTX3 is specifically recruited at both sides of the phagocytic synapse between dendritic cells (DCs) and dying cells and remains stably bound to the apoptotic membranes (estimated half-time > 36 hours). Apoptotic cells per se influence the production of PTX3 by maturing DCs. When both microbial stimuli and dying cells are present, PTX3 behaves as a flexible adaptor of DC function, regulating the maturation program and the secretion of soluble factors. Moreover a key event associated with autoimmunity (ie, the cross-presentation of epitopes expressed by apoptotic cells to T cells) abates in the presence of PTX3, as evaluated using self, viral, and tumor-associated model antigens (vinculin, NS3, and MelanA/MART1). In contrast, PTX3 did not influence the presentation of exogenous soluble antigens, an event required for immunity against extracellular pathogens. These data suggest that PTX3 acts as a third-party agent between microbial stimuli and dying cells, contributing to limit tissue damage under inflammatory conditions and the activation of autoreactive T cells.

Alterations during apoptosis lead to the activation of autoreactive T cells and the production of autoantibodies. This article discusses the pathogenic potential of cells dying in vivo, dissecting the role of signals that favor immune responses (adjuvants) and the influence of genetic backgrounds. Diverse factors determine whether apoptosis leads or not to a self-sustaining, clinically apparent autoimmune disease. The in vivo accumulation of uncleared dying cells per se is not sufficient to cause disease. However, dying cells are antigenic and their complementation with immune adjuvants causes lethal diseases in predisposed lupus-prone animals. At least some adjuvant signals directly target the function and the activation state of antigen presenting cells. Several laboratories are aggressively pursuing the molecular identification of endogenous adjuvants. Sodium monourate and the high mobility group B1 protein (HMGB1) are, among those identified so far, well known to rheumatologists. However, even the complementation of apoptotic cells with potent adjuvant signals fail to cause clinical autoimmunity in most strains: autoantibodies generated are transient, do not undergo to epitope/spreading and do not cause disease. Novel tools for drug development will derive from the molecular identification of the constraints that prevent autoimmunity in normal subjects.

Extract: Survival has always been a challenge in nature and fast adaptation is the key. To adapt to new situations during evolution, cells learned to reuse available molecules for different purposes. One example of a molecule recruited from an extant cellular pathway into new functions is the high mobility group box 1 (HMGB1) protein. Over the years, HMGB1 has been known by many names (amphoterin, differentiation enhancing factor, sulphoglucuronyl carbohydrate binding protein-1, p30) and relatively recently has been discovered to have a double identity from a functional point of view. When it resides in the nucleus, HMGB1 binds and bends the DNA helix facilitating the formation of protein complexes (multiple proteins binding to the same stretch of DNA) that regulate nuclear biochemical transactions. Once outside the cell it acts as a potent signal of inflammation, which is a fast response set in motion following injury or infection. The inflammatory reaction is mediated by the innate immune system, which constitutes the first line of defense to tissue damage and microbial agents. Processes like elimination of dead cells, protection against invading microorganisms and tissue repair intersect at the level of innate immunity. We will summarize recently published data that point towards HMGB1 as a common signal of tissue injury and infection used by the innate immune system, and highlight its involvement in disease.

Two of the main challenges that eukaryotic multicellular organisms faced during evolution were to eliminate and replace dying cells and to cope with invading microorganisms. The innate immune system evolved to handle both tasks: to scavenge cellular debris and to form the first line of defence against microbes. In this review, we focus on high mobility group box 1 (HMGB1) protein as a common signal that alerts the innate immune system to excessive or deregulated cell death and to microbial invasion. HMGB1, which is well known nuclear protein, has revealed unexpected facets as an extracellular mediator. The role of HMGB1 as an endogenous molecule that facilitates immune responses and has an important role in tissue homeostasis and disease will be highlighted here.

Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the best-characterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases.

High mobility group box 1 (HMGB1) is an abundant and conserved nuclear protein that is released by necrotic cells and acts in the extracellular environment as a primary proinflammatory signal. In this study we show that human dendritic cells, which are specialized in Ag presentation to T cells, actively release their own HMGB1 into the extracellular milieu upon activation. This secreted HMGB1 is necessary for the up-regulation of CD80, CD83, and CD86 surface markers of human dendritic cells and for IL-12 production. The HMGB1 secreted by dendritic cells is also required for the clonal expansion, survival, and functional polarization of naive T cells. Using neutralizing Abs and receptor for advanced glycation end product-deficient (RAGE(-/-)) cells, we demonstrate that RAGE is required for the effect of HMGB1 on dendritic cells. HMGB1/RAGE interaction results in downstream activation of MAPKs and NF-kappaB. The use of an ancient signal of necrosis, HMGB1, by dendritic cells to sustain their own maturation and for activation of T lymphocytes represents a profitable evolutionary mechanism.

Strategies to enhance the immunogenicity of tumors are urgently needed. Although vaccination with irradiated dying lymphoma cells recruits a tumor-specific immune response, its efficiency as immunogen is poor. Annexin V (AxV) binds with high affinity to phosphatidylserine on the surface of apoptotic and necrotic cells and thereby impairs their uptake by macrophages. Here, we report that AxV preferentially targets irradiated lymphoma cells to CD8+ dendritic cells for in vivo clearance, elicits the release of proinflammatory cytokines and dramatically enhances the protection elicited against the tumor. The response was endowed with both memory, because protected animals rejected living lymphoma cells after 72 d, and specificity, because vaccinated animals failed to reject unrelated neoplasms. Finally, AxV-coupled irradiated cells induced the regression of growing tumors. These data indicate that endogenous adjuvants that bind to dying tumor cells can be exploited to target tumors for immune rejection.

Depletion of dendritic cells (DCs) via apoptosis contributes to sepsis-induced immune suppression. The mechanisms leading to DC apoptosis during sepsis are not known. In this study we report that immature DCs undergo apoptosis when treated with high numbers of Escherichia coli. This effect was mimicked by high concentrations of LPS. Apoptosis was accompanied by generation of ceramide through activation of acid sphingomyelinase (A-SMase), was prevented by inhibitors of this enzyme, and was restored by exogenous ceramide. Compared with immature DCs, mature DCs expressed significantly reduced levels of A-SMase, did not generate ceramide in response to E. coli or LPS, and were insensitive to E. coli- and LPS-triggered apoptosis. However, sensitivity to apoptosis was restored by addition of exogenous A-SMase or ceramide. Furthermore, inhibition of A-SMase activation and ceramide generation was found to be the mechanism through which the immune-modulating messenger NO protects immature DCs from the apoptogenic effects of E. coli and LPS. NO acted through formation of cGMP and stimulation of the cGMP-dependent protein kinase. The relevance of A-SMase and its inhibition by NO/cGMP were confirmed in a mouse model of LPS-induced sepsis. DC apoptosis was significantly higher in inducible NO synthase-deficient mice than in wild-type animals and was significantly reduced by treatment ex vivo with NO, cGMP, or the A-SMase inhibitor imipramine. Thus, A-SMase plays a central role in E. coli/LPS-induced DC apoptosis and its inhibition by NO, and it might be a target of new therapeutic approaches to sepsis.

Objective: Phagocytosis of apoptotic cells can be facilitated by complement components and short pentraxins, such as serum amyloid P (SAP). In contrast, the long pentraxin PTX3 was shown to inhibit phagocytosis of apoptotic Jurkat cells by dendritic cells and to bind late apoptotic polymorphonuclear leukocytes (PMNs). Recently, levels of the pentraxin PTX3 were shown to parallel disease activity in small-vessel vasculitis, which is often characterized by leukocytoclasia, a persistence of leukocyte remnants in the vessel wall. We undertook this study to test our hypothesis that PTX3 inhibits phagocytosis of late apoptotic PMNs by macrophages, thereby leading to their accumulation in the vessel wall., Methods: Macrophages were allowed to phagocytose late apoptotic or secondary necrotic PMNs that were incubated with or without PTX3 for 30 minutes prior to phagocytosis. Phagocytosis was allowed to occur in the presence of 30% normal human serum with or without SAP and with or without depletion of complement. To discriminate between an inhibitory effect of PTX3 on binding and the internalization of apoptotic PMNs into macrophages, internalization was blocked by cytochalasin B., Results: SAP and complement were both necessary for effective in vitro phagocytosis. In contrast, PTX3 inhibited phagocytosis in a dose-dependent manner, from 11% inhibition at 6.25 microg/ml to almost complete inhibition at 100 microg/ml. Furthermore, PTX3 partly affected binding of apoptotic PMNs to macrophages., Conclusion: PTX3, in contrast to SAP and complement, inhibits phagocytosis of late apoptotic PMNs by monocyte-derived macrophages in a dose-dependent manner. Therefore, PTX3 can play a role in the development of leukocytoclasia by affecting the clearance of apoptotic PMNs, thereby inducing their accumulation in the vessel wall.

Immune responses against pathogens require that microbial components promote the activation of antigen-presenting cells (APCs). Autoimmune diseases and graft rejections occur in the absence of pathogens; in these conditions, endogenous molecules, the so-called 'innate adjuvants', activate APCs. Necrotic cells contain and release innate adjuvants; necrotic cells also release high-mobility group B1 protein (HMGB1), an abundant and conserved constituent of vertebrate nuclei. Here, we show that necrotic HMGB1(-/-) cells have a reduced ability to activate APCs, and HMGB1 blockade reduces the activation induced by necrotic wild-type cell supernatants. In vivo, HMGB1 enhances the primary antibody responses to soluble antigens and transforms poorly immunogenic apoptotic lymphoma cells into efficient vaccines.

Antigen presenting cells (APCs) activate helper and cytotoxic T cells specific for antigens expressed by tissue cells, including neoplastic cells. This event occurs after the antigen transfer from tissue cells to APC, and is referred to as "cross-presentation". The number and the state of activation of APC in the tumor control the outcome of cross-presentation, including the establishment of protective immune responses. Cell death favors cross-presentation. Cancer cells normally die, either spontaneously or as a consequence of targeted therapies. The transfer of tumor antigens from dying tumor cells to APCs in vivo, exploiting the cross-presentation pathway, has the potential of yielding novel immunotherapeutic strategies. Their success will depend on at least two factors: the induction of synchronized cell death in the tumor, and the recruitment of activated dendritic cells in the tumor. Under normal conditions, pancreatic cancer represents a privileged environment; its profound chemoresistance reflects limited apoptosis after chemotherapy. Moreover, it usually contains only a few cells endowed with APC function. Endoscopic ultrasonography offers attractive possibilities of circumventing this privilege, including the delivery of ultrasound, radiofrequency or radiation in order to destroy the tumor and the delivery in situ of autologous APC or appropriate chemotactic signals. In general, loco-regional approaches offer the possibility of using the tumor of each patient as a complex antigen source, thus limiting the risk of tumor escape and reducing the need for extensive ex vivo handling of the neoplasm and of the patient APCs.

Susceptibility of dendritic cells (DCs) to tumor-induced apoptosis reduces their efficacy in cancer therapy. Here we show that delivery within exponentially growing B16 melanomas of DCs treated ex vivo with nitric oxide (NO), released by the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), significantly reduced tumor growth, with cure of 37% of animals. DETA-NO-treated DCs became resistant to tumor-induced apoptosis because DETA-NO prevented tumor-induced changes in the expression of Bcl-2, Bax, and Bcl-xL; activation of caspase-9; and a reduction in the mitochondrial membrane potential. DETA-NO also increased DC cytotoxic activity against tumor cells and DC ability to trigger T-lymphocyte proliferation. All of the effects of DETA-NO were mediated through cGMP generation. NO and NO-generating drugs may therefore be used to increase the anticancer efficacy of DCs.

Objective: Cells commonly die without eliciting autoimmunity. However, dying cells are a potential initiating stimulus for systemic lupus erythematosus (SLE). Our goal was to verify whether immune adjuvants influence the autoimmunity induction that ensues following in vivo injection of dying cells., Methods: Mice were immunized with apoptotic thymocytes in the presence of artificial moieties, such as Freund's incomplete adjuvant (IFA), or natural adjuvants, such as dendritic cells (DCs). Renal involvement and the development of autoantibodies were monitored., Results: Apoptotic cells failed to induce clinical disease or to sustain production of autoantibodies in (NZB x NZW)F(1) mice. In contrast, autoimmunity developed in the presence of IFA or DCs. The characteristics of the adjuvant influenced the array of autoantibodies, the kinetics of their development, and the severity of the disease. DCs were required for induction of anti-beta(2)-glycoprotein I IgG. Adjuvants alone did not elicit disease., Conclusion: A "two-hit" signal composed of autoantigens and adjuvants initiates systemic autoimmunity. Moreover, environmental signals at the site of clearance of dead cells shape the features and the severity of the autoimmune disease. Strategies aimed at preventing the accumulation of dying cells and at modulating endogenous adjuvants may be beneficial for the treatment of SLE.

Objective: Patients undergoing anti-tumour necrosis factor-alpha (TNF-alpha) treatment often develop autoantibodies. Apoptotic cell antigens are a potential initiating stimulus for autoantibodies. Our goal was to verify whether anti-cytokine therapy causes the release of nucleosomes, a major autoantigen generated during cell death., Design: Laboratory research study with comparison group., Setting: Clinical Immunology Unit and Lab, H San Raffaele University Hospital, Italy., Subjects: Eleven healthy controls and 87 rheumatic patients were studied, including 51 with rheumatoid arthritis (RA) and 33 patients with systemic lupus erythematosus (SLE)., Interventions: Vein blood samples were taken via the antecubital vein. Blood was retrieved from 11 patients before and after injection of anti-TNF-alpha humanized antibodies. Nucleosomes were measured with an enzyme-linked immunosorbent assay. Cell death induced by anti-TNF-alpha antibodies and by the soluble cytokine was assessed in vitro., Main Outcome Measures: Nucleosome level by treatment., Results: Enzyme-linked immunosorbent assay effectively detected nucleosomes either released by dying cells in vitro or circulating in the plasma. SLE but not RA patients had circulating nucleosomes at the steady state. Eight of 11 patients had significantly higher levels of plasma nucleosomes after infliximab. Minute amounts of TNF-alpha enabled infliximab to induce cell death in vitro., Conclusions: The accumulation of nucleosomes possibly fosters the development of autoantibodies in subjects with appropriate genetic backgrounds.

The cross-presentation of Ags derived from apoptotic cell processing contributes to peripheral tolerance. Environmental signals possibly modify this default outcome, favoring cross-priming. In this study, we anchored via a biotin-avidin-biotin bridge soluble TNF-alpha to the membrane of apoptotic melanoma cells and studied in vivo and in vitro the interaction with Ag-presenting phagocytes. TNF-alpha-coated apoptotic melanoma cells injected s.c. had a faster and more efficient access to draining lymph nodes, with cross-priming of melanoma-specific CTLs and delayed outgrowth of melanomas in all treated animals. Twenty percent of the animals, in the absence of further adjuvant, did not develop the tumor. Immature dendritic cells challenged with TNF-alpha-coated apoptotic melanoma cells secreted proinflammatory cytokines in an autocrine/paracrine fashion, efficiently matured, as assessed functionally and by flow cytometry and cross-presented with enhanced efficiency melanoma Ags to MHC class I- and II-restricted T cells. The results indicate that TNF-alpha targeted to apoptotic membranes, at concentrations that can be safely reached in growing tumors without undue systemic toxicity, influences the outcome of the disposal of dying cells and enhances tumor immunogenicity.

The termination of the apoptotic program occurs in most cases via recognition and clearance by phagocytes. Engulfed cells do not simply disappear from the midst of living tissues. Constituents of the corpse indeed survive the intracellular processing and are recycled to the membrane of the phagocyte. The presentation of yielded antigens to T cells is a central event in the induction and the maintenance of peripheral tolerance. Conversely, errors in this pathway contribute to the pathogenesis of systemic and organ specific autoimmune diseases. Here we discuss the available information on the events that follow active engulfment of dying cells, with attention to the events involved in vitro and in vivo in apoptotic cell processing. The outcome of the processing is the cross-priming or the functional inactivation of T cells that specifically recognise antigens contained in the cell corpse.

The physiologic clearance of apoptotic cells prevents inflammation at the site of cell death and limits the immunogenicity of tumors. In this study we report the functional characterisation of biotinylated tumor necrosis factor-alpha (TNF-alpha) after anchorage to apoptotic melanoma cells via a biotin-avidin-biotin bridge. Flow cytometric and morphological analysis showed that biotinylated TNF-alpha efficiently bound to apoptotic membrane blebs of dying cells. Membrane-bound TNF-alpha (12 fg/cell) killed sensitive WEHI164 cells 250-fold more effectively than equivalent amounts of the soluble cytokine. Furthermore, macrophages engulfing apoptotic cells with membrane-bound TNF-alpha secreted significantly higher amounts of soluble TNF-alpha and lower amounts of interleukin-10 (IL-10). Therefore the bridging of TNF-alpha potentiates its biological function and influences the outcome of the phagocytic clearance of apoptotic tumor cells.

Nitric oxide (NO), generated by phagocytes at inflammation sites, contributes to regulate immune responses through autocrine and paracrine actions on bystander cells. Among the latter are dendritic cells (DCs). Little is known about regulation of DC function by NO, especially in the human system. We exposed human monocyte-derived DCs to the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) during their maturation process induced by treatment with tumor necrosis factor alpha or lipopolysaccharide or by CD40 activation. We report here that after exposure to DETA-NO, DCs exhibit a significantly increased ability to activate T lymphocytes stimulated by mycobacterial antigens, Staphylococcus aureus Cowen strain B, allo-antigens, or cross-linking of the CD3-T cell receptor complex. This effect persists after removal of DETA-NO, depends on the generation of cyclic guanosine 5'-monophosphate, and is a result of enhanced release by DCs of soluble factors, in particular interleukin (IL)-12. This modulation of DC function is a result of a synergism between NO and the various maturation stimuli, as neither enhanced T cell activation nor IL-12 release was observed after DC exposure to DETA-NO only. These results provide the first evidence that NO acts as a cosignaling molecule regulating human DC response to maturation stimuli.

Autoimmunity represents a caveat to the use of dendritic cells (DCs) as adjuvant for human vaccines. We derived DCs from normal BALB/c mice or from mice prone to autoimmunity (NZB x NZW) F(1). We allowed DCs to phagocytose apoptotic thymocytes and vaccinated syngeneic animals. All mice developed anti-nuclear and anti-dsDNA Abs. Autoantibodies in normal mice were transient, without clinical or histological features of autoimmunity or tissue involvement. In contrast, autoimmunity was maintained in susceptible mice, which underwent renal failure and precociously died. The data suggest that DC vaccination consistently triggers autoimmune responses. However, clinical autoimmunity develops in susceptible subjects only.

Cells continuously die and disappear from the midst of living tissues. However, some of their constituents survive. DNA is horizontally transferred to phagocytic cells, and apoptotic cell antigens shape the immune repertoire. When massive apoptosis occurs, which overwhelms tissue scavenger cells, or when the function of phagocytes abates, dying cells escape clearance in vivo. Remnant dying cells come to phagocytes disguised: factors capable to envelop their membranes pervade the entire organism, or are generated in given tissues. Some are constitutively present, while other are generated during early or late phases of the inflammatory response, possibly to face the further burden of the dead inflammatory cells. This camouflage influences the disposal of the corpses: decoying molecules either bridge the corpse to the phagocyte or hide it. Furthermore, factors associated to the plasma membrane of the apoptotic cell shape the signals the phagocyte releases in situ. Finally, molecules contained or released by the dying cell alter the apprehension by the phagocyte of its prey, influencing its immunogenicity.