Sterile inflammation: sensing and reacting to damage

In the paper

“In ischaemia–reperfusion injury, as seen with myocardial infarction and stroke, the restoration of blood flow causes further tissue destruction as a result of neutrophilic infiltration, enhanced production of ROS and inflammatory responses to necrotic cells2.”

What the sources say

• Not checked yetcites [2] Cotran, R. S., Kumar, V. & Robbins, S. in Robbins Pathologic Basis of Disease (ed. Schoen, F. J.) 6–11 (W. B. Saunders Company, Philadelphia, 1994).

In the paper

“It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns.”

In the paper

“Sterile inflammation has also been implicated in such disease processes as gout and pseudogout, in which the deposition of monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals in the joints results in acute neutrophilic infiltration followed by chronic inflammation, fibrosis and cartilage destruction3.”

What the sources say

• Not checked yetcites [3] Cotran, R. S., Kumar, V. & Robbins, S . in Robbins Pathologic Basis of Disease (ed. Schoen, F. J.) 1255–1259 (W. B. Saunders Company, Philadelphia, 1994).

In the paper

“Chronic inhalation of sterile irritants, such as asbestos and silica, can lead to persistent activation of alveolar macrophages and result in pulmonary interstitial fibrosis1.”

What the sources say

• Not checked yetcites [1] Mossman, B. T. & Churg, A. Mechanisms in the pathogenesis of asbestosis and silicosis. Am. J. Respir. Crit. Care Med. 157, 1666–1680 (1998). source

In the paper

“For example, there is evidence for a role of TLR2 and/or TLR4 in the induction of cytokine and chemokine production in response to extracellular matrix components, including hyaluronan fragments or soluble proteoglycan components, in vitro and in vivo31–34.”

What the sources say

• Not checked yetcites [31] Jiang, D. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nature Med. 11, 1173–1179 (2005). This paper shows the dual role of TLRs in mediating sterile inflammation in response to hyaluronan fragments released during injury and in promoting tissue repair. source
• Not checked yetcites [32] Scheibner, K. A. et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J. Immunol. 177, 1272–1281 (2006). source
• Not checked yetcites [33] Schaefer, L. et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J. Clin. Invest. 115, 2223–2233 (2005). source
• Not checked yetcites [34] Kim, S. et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009). source

In the paper

“There is mounting evidence that TLRs sense endogenous molecules in addition to microbial PAMPs.”

In the paper

“Moreover, inflammatory responses during infection are very similar to responses induced by sterile stimuli, including the recruitment of neutrophils and macrophages, the production of inflammatory cytokines and chemokines, and the induction of T cell-mediated adaptive immune responses23.”

What the sources say

• Not checked yetcites [23] Mbitikon-Kobo, F. M. et al. Characterization of a CD44/CD122int memory CD8 T cell subset generated under sterile inflammatory conditions. J. Immunol. 182, 3846–3854 (2009). source

In the paper

“In one study, treatment of mice with HMGb1-specific antibodies during acetaminophen-induced liver necrosis ameliorated inflammatory cell recruitment10.”

What the sources say

• Not checked yetcites [10] Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002). source

In the paper

“Sterile inflammation is also an important component of atherosclerosis, as engulfment of cholesterol crystals by macrophages leads to the activation and recruitment of inflammatory cells, endothelial cell dysfunction and plaque formation5.”

What the sources say

• Not checked yetcites [5] Ross, R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999). source

In the paper

“However, in a peritoneal model of sterile inflammation, there was no difference between wild-type and HMGb1-deficient necrotic cells in their ability to promote neutrophilic recruitment22.”

What the sources say

• Not checked yetcites [22] Chen, C. J. et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Med. 13, 851–856 (2007). This paper demonstrates a crucial role for IL-1α in sterile inflammation and, in particular, neutrophil recruitment induced by necrotic cells. source

In the paper

“However, this does not exclude a role for TLR signalling in other models of sterile inflammation.”

In the paper

“Indeed, several endogenous molecules that are released from necrotic cells or are present in the extracellular matrix have been reported to activate TLRs.”

What the sources say

• Not checked yetcites [17] Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nature Rev. Immunol. 8, 279–289 (2008). source

In the paper

“Prototypical DAMPs derived from necrotic cells include the chromatin-associated protein high-mobility group box 1 (HMGb1)10, heat shock proteins (HSPs)11, and purine metabolites, such as ATP12 and uric acid13 (TABLE 1).”

What the sources say

• Not checked yetcites [10] Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002). source
• Not checked yetcites [11] Quintana, F. J. & Cohen, I. R. Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J. Immunol. 175, 2777–2782 (2005). source
• Not checked yetcites [12] Bours, M. J., Swennen, E. L., Di Virgilio, F., Cronstein, B. N. & Dagnelie, P. C. Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther. 112, 358–404 (2006). source

In the paper

“Deficiency in either TLR2 or TLR4 signalling also reduced atherosclerotic disease in mouse models35–37, and TLR4, specifically, has been shown to mediate inflammatory responses to free fatty acids,”

What the sources say

• Not checked yetcites [35] Mullick, A. E., Tobias, P. S. & Curtiss, L. K. Modulation of atherosclerosis in mice by Toll-like receptor 2. J. Clin. Invest. 115, 3149–3156 (2005). source
• Not checked yetcites [36] Michelsen, K. S. et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Natl Acad. Sci. USA 101, 10679–10684 (2004). source
• Not checked yetcites [37] Bjorkbacka, H. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature Med. 10, 416–421 (2004). source

In the paper

“the relevance of these observations has previously been questioned because of the possibility of microbial contamination: several of these proteins, including HSPs and HMGb1, bind lipopolysaccharide (LPS), making the interpretation of pro-inflammatory responses by these molecules difficult28–30.”

What the sources say

• Not checked yetcites [28] Gao, B. & Tsan, M. F. Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70) preparation is responsible for the induction of tumor necrosis factor α release by murine macrophages. J. Biol. Chem. 278, 174–179 (2003). source
• Not checked yetcites [29] Rouhiainen, A., Tumova, S., Valmu, L., Kalkkinen, N. & Rauvala, H. Pivotal advance: analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). J. Leukoc. Biol. 81, 49–58 (2007). source
• Not checked yetcites [30] Youn, J. H., Oh, Y. J., Kim, E. S., Choi, J. E. & Shin, J. S. High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-α production in human monocytes. J. Immunol. 180, 5067–5074 (2008). source

In the paper

“As the inflammation induced in response to sterile cell death or injury is similar to that observed during microbial infection, host receptors that mediate the immune response to microorganisms may be involved in the activation of sterile inflammation.”

In the paper

“because mice lacking TLR2 and TLR4 have only a slight reduction in the peritoneal inflammatory response to sterile dead cells in vivo22, a reasonable conclusion is that TLR2–TLR4 signalling is not the main mechanism by which intracellular factors induce inflammatory responses to necrotic cell death.”

What the sources say

• Not checked yetcites [22] Chen, C. J. et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Med. 13, 851–856 (2007). This paper demonstrates a crucial role for IL-1α in sterile inflammation and, in particular, neutrophil recruitment induced by necrotic cells. source

In the paper

“The possibility that mammalian TLRs recognize non-microbial structures is not unexpected, because the evolutionarily conserved Toll receptor originally identified in Drosophila melanogaster binds to the endogenous ligand Spätzle24.”

What the sources say

• Not checked yetcites [24] Weber, A. N. et al. Binding of the Drosophila cytokine Spatzle to Toll is direct and establishes signaling. Nature Immunol. 4, 794–800 (2003). source

In the paper

“Although several of the purified endogenous molecules, including HSPs, HMGb1 and uric acid, can induce the production of pro-inflammatory cytokines through TLR2 and/or TLR4 in vitro25–27, the relevance of these observations has previously been questioned because of the possibility of microbial contamination: several of these proteins, including HSPs and HMGb1, bind lipopolysaccharide (LPS), making”

What the sources say

• Not checked yetcites [25] Vabulas, R. M. et al. Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells. J. Biol. Chem. 276, 31332–31339 (2001). source
• Not checked yetcites [26] Yu, M. et al. HMGB1 signals through Toll-like receptor (TLR) 4 and TLR2. Shock 26, 174–179 (2006). source
• Not checked yetcites [27] Liu-Bryan, R., Scott, P., Sydlaske, A., Rose, D. M. & Terkeltaub, R. Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum. 52, 2936–2946 (2005). source

In the paper

“Furthermore, many DAMPs, such as HSPs and HMGb1, seem to interact with several receptors (TABLE 1) and, therefore, the significance of these interactions during sterile inflammation and disease pathogenesis remains to be fully elucidated.”

What the sources say

• Not checked yetcites TABLE 1

In the paper

“This suggests that both infectious and sterile stimuli may function through common receptors and pathways.”

In the paper

“Similarly, in addition to intracellular molecules, intracellular stores of biologically active pro-inflammatory cytokines and chemokines, such as IL-1α15 and IL-33 (REF. 16), may be released by necrotic cells.”

What the sources say

• Not checked yetcites [15] Eigenbrod, T., Park, J. H., Harder, J., Iwakura, Y. & Nunez, G. Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells. J. Immunol. 181, 8194–8198 (2008). This paper shows that the passive release of IL-1α from necrotic cells, in particular necrotic dendritic cells, is important for the recruitment of neutrophils in the sterile inflammatory response through the production of CXCL1 by cells responsive to IL-1α. source
• Not checked yetcites [16] Moussion, C., Ortega, N. & Girard, J. P. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One 3, e3331 (2008). source

In the paper

“For example, a reduction of uric acid, which is released from dying cells and has adjuvant activity in vivo21, was associated with substantially reduced neutrophil recruitment in the liver after acetaminophen-induced injury in two different mouse models13.”

What the sources say

• Not checked yetcites [13] Kono, H., Chen, C. J., Ontiveros, F. & Rock, K. L. Uric acid promotes an acute inflammatory response to sterile cell death in mice. J. Clin. Invest. 120, 1939–1949 (2010). source
• Not checked yetcites [21] Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003). source

In the paper

“In Alzheimer's disease, neurotoxicity is associated with activated microglial cells adjacent to β-amyloid-containing plaques that generate ROS in addition to pro-inflammatory cytokines4.”

What the sources say

• Not checked yetcites [4] Weiner, H. L. & Frenkel, D. Immunology and immunotherapy of Alzheimer's disease. Nature Rev. Immunol. 6, 404–416 (2006). source

In the paper

“In the liver, which is normally devoid of microbial exposure, TLR9 has been implicated in triggering cytokine production and hepatocyte toxicity in acetaminophen-induced injury40.”

What the sources say

• Not checked yetcites [40] Imaeda, A. B. et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J. Clin. Invest. 119, 305–314 (2009).

In the paper

“P2RX7-dependent pore formation is not a prerequisite for NLRP3 activation by all stimuli.”

In the paper

“The AIM2 inflammasome has been recently shown to recognize cytoplasmic double-stranded DNA (dsDNA) that is not necessarily microbial in origin, resulting in caspase 1 activation and IL-1β secretion48–50.”

What the sources say

• Not checked yetcites [48] Burckstummer, T. et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nature Immunol. 10, 266–272 (2009). source
• Not checked yetcites [49] Fernandes-Alnemri, T., Yu, J. W., Datta, P., Wu, J. & Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009). source
• Not checked yetcites [50] Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009). source

In the paper

“In vitro, robust activation of the NLRP3 inflammasome in phagocytic cells that were pretreated with microbial products or cytokines such as TNF is dependent on the presence of ATP20.”

What the sources say

• Not checked yetcites [20] Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006). source

In the paper

“Also, necrotic cells can activate NLRP3, which is partly dependent on actively respiring mitochondria and the physiological release of ATP60.”

What the sources say

• Not checked yetcites [60] Iyer, S. S. et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl Acad. Sci. USA 106, 20388–20393 (2009). source

In the paper

“For these sterile particulates to activate NLRP3, they must be internalized, as blockade of endocytosis by the actin-depolymerizing drug cytochalasin D inhibited NLRP3-dependent IL-1β production58,59.”

What the sources say

• Not checked yetcites [58] Cassel, S. L. et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl Acad. Sci. USA 105, 9035–9040 (2008). source
• Not checked yetcites [59] Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010). source

In the paper

“It is probable that additional factors besides ATP have a role60.”

What the sources say

• Not checked yetcites [60] Iyer, S. S. et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl Acad. Sci. USA 106, 20388–20393 (2009). source

In the paper

“Crystal-induced arthropathies, such as gout, are associated with elevated IL-1β production, which leads to joint inflammation and destruction5.”

What the sources say

• Not checked yetcites [5] Ross, R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999). source

In the paper

“Therefore, it is posited that NLRP3 does not recognize each stimulus individually, but senses a common downstream event.”

In the paper

“In this model of sterile inflammation, activation of TLR9 is presumably mediated by genomic DNA released from necrotic hepatocytes40.”

What the sources say

• Not checked yetcites [40] Imaeda, A. B. et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J. Clin. Invest. 119, 305–314 (2009).

In the paper

“NLRP3 has been shown to respond to sterile stimuli, including asbestos, silica, MSU and CPPD crystals55, cholesterol crystals and β-amyloid fibrils56.”

What the sources say

• Not checked yetcites [55] Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). This study is one of the first to identify an endogenous, non-microbial signal for NLPR3 inflammasome activation that can lead to a non-infectious inflammatory disease (in this case, gout). source
• Not checked yetcites [56] Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008). source

In the paper

“Although distinct from NLRs, AIM2 has a pyrin domain that allows it to interact with the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) to form the inflammasome50.”

What the sources say

• Not checked yetcites [50] Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009). source

In the paper

“A potential role for NLRP3 in promoting elevated levels of IL-1β in type 2 diabetes was also implied by the observation of NLRP3-dependent IL-1β secretion by mouse bone marrow-derived macrophages and dendritic cells in response to islet amyloid polypeptide (IAPP), which is deposited in the pancreas and associated with loss of β-cell function in type 2 diabetes61.”

What the sources say

• Not checked yetcites [61] Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nature Immunol. 11, 897–904 (2010). source

In the paper

“Consistently, inhibition of K+ efflux by high extracellular K+ concentrations prevents NLRP3-dependent caspase 1 activation in response to ATP, asbestos, silica and MSU crystals58,66.”

What the sources say

• Not checked yetcites [58] Cassel, S. L. et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl Acad. Sci. USA 105, 9035–9040 (2008). source
• Not checked yetcites [66] Petrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007). source

In the paper

“A unique feature of NLRP3 is its ability to sense various structurally diverse stimuli.”

In the paper

“Consistently, in mouse models of sterile injury, such as gout, asbestosis and silicosis, NLRP3-deficient mice exhibited decreased inflammation with reduced levels of tissue infiltration by neutrophils or macrophages55,57,58.”

What the sources say

• Not checked yetcites [55] Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). This study is one of the first to identify an endogenous, non-microbial signal for NLPR3 inflammasome activation that can lead to a non-infectious inflammatory disease (in this case, gout). source
• Not checked yetcites [57] Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008). This study led to the model of NLRP3 activation that is dependent on the sensing of ROS, and demonstrated a role for NLRP3 in asbestosis. source
• Not checked yetcites [58] Cassel, S. L. et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl Acad. Sci. USA 105, 9035–9040 (2008). source

In the paper

“Urate and cholesterol crystals, as well as sterile particulates, for example, can bypass the requirement for ATP and P2RX7 for IL-1β production55,59.”

What the sources say

• Not checked yetcites [55] Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). This study is one of the first to identify an endogenous, non-microbial signal for NLPR3 inflammasome activation that can lead to a non-infectious inflammatory disease (in this case, gout). source
• Not checked yetcites [59] Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010). source

In the paper

“AIM2 has a demonstrated role in immune responses directed against both bacteria51 and DNA viruses52, but it will be important to determine whether there is a physiological role for AIM2 in sterile inflammation, especially in autoimmune diseases such as systemic lupus erythematosus, which is associated with elevated circulating levels of dsDNA.”

What the sources say

• Not checked yetcites [51] Fernandes-Alnemri, T. et al. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nature Immunol. 11, 385–393 (2010). source
• Not checked yetcites [52] Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunol. 11, 395–402 (2010). source

In the paper

“However, the role of TXNIP and ROS in NLRP3 activation has been challenged.”

What the sources say

• Not checked yetcites [61] Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nature Immunol. 11, 897–904 (2010). source

In the paper

“Furthermore, there is only partial inhibition of the neutrophil infiltration and IL-1β production associated with sterile inflammation in response to cholesterol crystals44,56,59,67.”

What the sources say

• Not checked yetcites [44] Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008). This study was pivotal in providing a model of NLRP3 activation that involves lysosomal damage and cathepsin B activation. source
• Not checked yetcites [56] Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008). source
• Not checked yetcites [59] Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010). source

In the paper

“Thus, the sensing of ROS may be a unifying mechanism by which NLRP3 senses its various activators.”

In the paper

“Subsequently, it was shown that IL-1α released by necrotic cells was crucial for the production of CXCL1, which recruits neutrophils, by non-haematopoietic cells such as mesothelial cells15.”

What the sources say

• Not checked yetcites [15] Eigenbrod, T., Park, J. H., Harder, J., Iwakura, Y. & Nunez, G. Cutting edge: critical role for mesothelial cells in necrosis-induced inflammation through the recognition of IL-1α released from dying cells. J. Immunol. 181, 8194–8198 (2008). This paper shows that the passive release of IL-1α from necrotic cells, in particular necrotic dendritic cells, is important for the recruitment of neutrophils in the sterile inflammatory response through the production of CXCL1 by cells responsive to IL-1α. source

In the paper

“Therefore, the detrimental effect of ROS during sterile inflammation depends on the balance between ROS producers and ROS inactivators.”

In the paper

“Furthermore, mouse macrophages that are deficient in p22phox (L. Franchi and G.N., unpublished observations) or the Gp91phox subunit of NADPH oxidase cytochrome b, which is a major generator of ROS in the cell, had normal, rather than decreased, levels of caspase 1 activation in response to ATP, silica or MSU crystals44.”

What the sources say

• Not checked yetcites [44] Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008). This study was pivotal in providing a model of NLRP3 activation that involves lysosomal damage and cathepsin B activation. source

In the paper

“Stimulation of CLRs typically results in the induction of signalling pathways that, in some cases, can synergize with TLR signalling pathways to upregulate cytokine and chemokine production.”

In the paper

“Similar to CLeC4e, the ability of CLeC9A to recognize necrotic cells makes it a potential receptor that is important for sterile inflammatory responses.”

In the paper

“There is evidence that the passive release of cytokines during sterile cell injury has a role in disease.”

In the paper

“The passive release of biologically active cytokines during sterile injury-associated cell death is an important mechanism to alert the immune system of tissue damage and to initiate the healing response.”

In the paper

“Thus, the relevance of ROS generation in NLRP3 activation in vivo remains unclear.”

In the paper

“Two cytokines of the IL-1 family, IL-1α and IL-33, are particularly relevant.”

In the paper

“However, cathepsin b-deficient macrophages have no impairment in IL-1β production in response to certain NLRP3 agonists, including LPS plus ATP, or MSU crystals, despite the impairment in their response to silica44,56,59,67.”

What the sources say

• Not checked yetcites [44] Hornung, V. et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunol. 9, 847–856 (2008). This study was pivotal in providing a model of NLRP3 activation that involves lysosomal damage and cathepsin B activation. source
• Not checked yetcites [56] Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008). source
• Not checked yetcites [59] Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010). source

In the paper

“In a model of high levels of cell death in the thymus by whole-body irradiation, CXCL2 production by thymic macrophages, as well as neutrophil infiltration into the thymus, was significantly suppressed in mice treated with a blocking antibody to CLeC4e73.”

What the sources say

• Not checked yetcites [73] Cambi, A. & Figdor, C. Necrosis: C-type lectins sense cell death. Curr. Biol. 19, R375–R378 (2009). source

In the paper

“How ROS production is sensed by NLRP3 is unknown, but it was recently shown in one study that NLRP3 interacts in a ROS-dependent manner with thioredoxin-interacting protein (TXNIP), which dissociates from the antioxidant enzyme thioredoxin during oxidative stress62.”

What the sources say

• Not checked yetcites [62] Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nature Immunol. 11, 136–140 (2010). source

In the paper

“Although their primary importance is in host defence against pathogens, CLRs can sense necrotic cell death72.”

What the sources say

• Not checked yetcites [72] Yamasaki, S. et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nature Immunol. 9, 1179–1188 (2008). source

In the paper

“CLeC9A (also known as DNGR1), which is expressed by CD8α+ dendritic cells, is also involved in the recognition of necrotic cells.”

In the paper

“In antigen-presenting cells, they are involved in antigen uptake and trafficking for antigen presentation71.”

What the sources say

• Not checked yetcites [71] Figdor, C. G., van Kooyk, Y. & Adema, G. J. C-type lectin receptors on dendritic cells and Langerhans cells. Nature Rev. Immunol. 2, 77–84 (2002). source

In the paper

“In a separate study, no differences in IL-1β secretion were observed between wild-type and TXNIP-deficient bone marrow-derived macrophages in response to several NLRP3 stimuli, including MSU crystals and ATP61.”

What the sources say

• Not checked yetcites [61] Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nature Immunol. 11, 897–904 (2010). source

In the paper

“In addition, IL-1α released during hepatocyte necrosis contributes to carcinogen-induced liver tumorigenesis in mice77.”

What the sources say

• Not checked yetcites [77] Sakurai, T. et al. Hepatocyte necrosis induced by oxidative stress and IL-1α release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14, 156–165 (2008). source

In the paper

“An additional damage signal that has been associated with NLRP3 stimulation and caspase 1 activation is ROS.”

In the paper

“In the case of IL-1α, its release from injured endothelial cells promotes allogeneic T cell infiltration in a mouse–human chimeric model of artery allograft rejection76.”

What the sources say

• Not checked yetcites [76] Rao, D. A. et al. Interleukin (IL)-1 promotes allogeneic T cell intimal infiltration and IL-17 production in a model of human artery rejection. J. Exp. Med. 205, 3145–3158 (2008). source

In the paper

“Interestingly, Clec4e mRNA is upregulated in patients with rheumatoid arthritis73,74.”

What the sources say

• Not checked yetcites [73] Cambi, A. & Figdor, C. Necrosis: C-type lectins sense cell death. Curr. Biol. 19, R375–R378 (2009). source
• Not checked yetcites [74] Nakamura, N. et al. Isolation and expression profiling of genes upregulated in bone marrow-derived mononuclear cells of rheumatoid arthritis patients. DNA Res. 13, 169–183 (2006). source

In the paper

“In addition, the binding of β-amyloid to RAGe results in activated microglial cells94, and RAGe expression by microglial cells contributed to neuroinflammation in a mouse model of Alzheimer's disease89.”

What the sources say

• Not checked yetcites [89] Fang, F. et al. RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB J. 24, 1043–1055 (2009). source

In the paper

“The protein contains no obvious signalling domains90, although extracellular signal-regulated kinase (eRK) was shown to directly interact with the cytoplasmic tail of RAGe97.”

What the sources say

• Not checked yetcites [90] Sims, G. P., Rowe, D. C., Rietdijk, S. T., Herbst, R. & Coyle, A. J. HMGB1 and RAGE in inflammation and cancer. Annu. Rev. Immunol. 28, 367–388 (2010). source

In the paper

“In addition to AGes, RAGe also recognizes HMGb193 and the S100 family members19, which are released during cellular stress and necrotic cell death, and β-amyloid94, the accumulation of which is pathogenic in Alzheimer's disease.”

What the sources say

• Not checked yetcites [94] Yan, S. D. et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996). source

In the paper

“As in the case of TLR9 and RAGe, some of these receptors engage TLRs to form co-receptor complexes, which then induce inflammatory responses through TLR-dependent pathways.”

In the paper

“In addition, the binding of β-amyloid to RAGe results in activated microglial cells94, and RAGe expression by microglial cells contributed to neuroinflammation in a mouse model of Alzheimer's disease89.”

What the sources say

• Not checked yetcites [94] Yan, S. D. et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996). source

In the paper

“In the case of necrotic liver tissue, IL-1α and IL-1β derived from resident macrophages, but not the necrotic cells themselves, seem to have a crucial role in eliciting the neutrophilic response41.”

What the sources say

• Not checked yetcites [41] Kono, H., Karmarkar, D., Iwakura, Y. & Rock, K. L. Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death. J. Immunol. 184, 4470–4478 (2010). This study shows the crucial role for macrophages in mediating the inflammatory response to sterile cell death, such as by IL-1α production. source

In the paper

“Several other non-PRRs have been shown to interact with certain DAMPs, although their precise roles during sterile inflammation in vivo have not been verified.”

In the paper

“In certain cases, RAGe may transduce signals by acting cooperatively with TLRs.”

What the sources say

• Not checked yetcites [98] Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007). source

In the paper

“Hyaluronan is also directly recognized by TLR2 and TLR4, and this interaction was shown to have a role in mediating inflammatory responses in a mouse model of sterile bleomycin-induced lung injury102.”

What the sources say

• Not checked yetcites [102] Jiang, D., Liang, J. & Noble, P. W. Hyaluronan in tissue injury and repair. Annu. Rev. Cell Dev. Biol. 23, 435–461 (2007). source

In the paper

“In addition to PRRs, DAMPs are recognized by DAMP-specific receptors.”

In the paper

“RAGe has been implicated in both diabetes- and obesity-related atherosclerosis using apolipoprotein e (APOe)-deficient mice, which are susceptible to developing atherosclerosis99,100.”

What the sources say

• Not checked yetcites [99] Ueno, H. et al. Receptor for advanced glycation end-products (RAGE) regulation of adiposity and adiponectin is associated with atherogenesis in apoE-deficient mouse. Atherosclerosis 211, 431–436 (2010). source
• Not checked yetcites [100] Soro-Paavonen, A. et al. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes 57, 2461–2469 (2008). source

In the paper

“extracellular IL-33 that is released during necrosis also functions as an alarmin to alert cells, such as mast cells and other innate immune cells, to tissue damage85,86.”

What the sources say

• Not checked yetcites [85] Luthi, A. U. et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98 (2009). source
• Not checked yetcites [86] Cayrol, C. & Girard, J. P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl Acad. Sci. USA 106, 9021–9026 (2009). source

In the paper

“Hyaluronan is also directly recognized by TLR2 and TLR4, and this interaction was shown to have a role in mediating inflammatory responses in a mouse model of sterile bleomycin-induced lung injury102.”

What the sources say

• Not checked yetcites [102] Jiang, D., Liang, J. & Noble, P. W. Hyaluronan in tissue injury and repair. Annu. Rev. Cell Dev. Biol. 23, 435–461 (2007). source

In the paper

“Similar to IL-1α, IL-33 is active as a precursor protein.”

In the paper

“IL-33-deficient mice have reduced neutrophil migration in an experimental model of rheumatoid arthritis88, but the actual role of this cytokine in the pathogenesis of rheumatoid arthritis or other sterile inflammatory diseases remains to be determined.”

What the sources say

• Not checked yetcites [88] Verri, W. A. Jr et al. IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy. Ann. Rheum. Dis. 69, 1697–1703 (2010). source

In the paper

“IL-33 is highly expressed within endothelial cells in the synovium of patients with rheumatoid arthritis87, and IL-33-deficient mice have reduced neutrophil migration in an experimental model of rheumatoid arthritis88, but the actual role of this cytokine in the pathogenesis of rheumatoid arthritis or other sterile inflammatory diseases remains to be determined.”

What the sources say

• Not checked yetcites [87] Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl Acad. Sci. USA 104, 282–287 (2007). source

In the paper

“It detects advanced glycation end-products (AGes) that arise from non-enzymatic glycation and oxidation of proteins and lipids.”

What the sources say

• Not checked yetcites [92] Bucciarelli, L. G. et al. RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease. Cell. Mol. Life Sci. 59, 1117–1128 (2002). source

In the paper

“In addition to AGes, RAGe also recognizes HMGb193 and the S100 family members19, which are released during cellular stress and necrotic cell death, and β-amyloid94, the accumulation of which is pathogenic in Alzheimer's disease.”

What the sources say

• Not checked yetcites [19] Hofmann, M. A. et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97, 889–901 (1999). source

In the paper

“RAGe is a transmembrane receptor that is expressed by immune cells, endothelial cells, cardiomyocytes and neurons89–91.”

What the sources say

• Not checked yetcites [89] Fang, F. et al. RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB J. 24, 1043–1055 (2009). source
• Not checked yetcites [90] Sims, G. P., Rowe, D. C., Rietdijk, S. T., Herbst, R. & Coyle, A. J. HMGB1 and RAGE in inflammation and cancer. Annu. Rev. Immunol. 28, 367–388 (2010). source
• Not checked yetcites [91] Shang, L. et al. RAGE modulates hypoxia/reoxygenation injury in adult murine cardiomyocytes via JNK and GSK-3β signaling pathways. PLoS One 5, e10092 (2010). source

In the paper

“Hyaluronan fragments, for example, can signal through CD44, leading to MAPK activation102.”

What the sources say

• Not checked yetcites [102] Jiang, D., Liang, J. & Noble, P. W. Hyaluronan in tissue injury and repair. Annu. Rev. Cell Dev. Biol. 23, 435–461 (2007). source

In the paper

“Although it was initially thought that the IL-33 precursor was processed by caspase 1 to produce biologically active IL-33, it is now clear that its processing by the executioner caspases caspase 3 and caspase 7 during apoptosis inactivates IL-33 (REFS 85,86).”

What the sources say

• Not checked yetcites [85] Luthi, A. U. et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98 (2009). source
• Not checked yetcites [86] Cayrol, C. & Girard, J. P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl Acad. Sci. USA 106, 9021–9026 (2009). source

In the paper

“Furthermore, blockade of RAGe by using a soluble competitive inhibitor suppressed diabetes-associated atherosclerosis in mouse models92.”

What the sources say

• Not checked yetcites [92] Bucciarelli, L. G. et al. RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease. Cell. Mol. Life Sci. 59, 1117–1128 (2002). source

In the paper

“Activation of RAGe by its ligands results in the upregulation of several inflammatory signalling pathways, including, but not limited to, NF-κb, phospho inositide 3-kinase, Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and MAPK signalling pathways, which lead to induction of pro-inflammatory cytokines such as TNF19,91,95,96.”

What the sources say

• Not checked yetcites [19] Hofmann, M. A. et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97, 889–901 (1999). source
• Not checked yetcites [91] Shang, L. et al. RAGE modulates hypoxia/reoxygenation injury in adult murine cardiomyocytes via JNK and GSK-3β signaling pathways. PLoS One 5, e10092 (2010). source
• Not checked yetcites [95] Huang, J. S. et al. Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. J. Cell Biochem. 81, 102–113 (2001). source
• Not checked yetcites [96] Dukic-Stefanovic, S., Schinzel, R., Riederer, P. & Munch, G. AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs? Biogerontology 2, 19–34 (2001). source

In the paper

“In addition to AGes, RAGe also recognizes HMGb193 and the S100 family members19, which are released during cellular stress and necrotic cell death, and β-amyloid94, the accumulation of which is pathogenic in Alzheimer's disease.”

What the sources say

• Not checked yetcites [93] Hori, O. et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J. Biol. Chem. 270, 25752–25761 (1995). source

In the paper

“For example, necrotic dendritic cells, but not necrotic macrophages, heart cells or liver cells, rely on IL-1α to recruit neutrophils, at least in a peritonitis model41.”

What the sources say

• Not checked yetcites [41] Kono, H., Karmarkar, D., Iwakura, Y. & Rock, K. L. Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death. J. Immunol. 184, 4470–4478 (2010). This study shows the crucial role for macrophages in mediating the inflammatory response to sterile cell death, such as by IL-1α production. source

In the paper

“Specifically, HMGb1-bound DNA can form a complex with TLR9 and RAGe to induce pro-inflammatory cytokines98, which may be important for promoting inflammation in patients with systemic lupus erythematosus who have elevated circulating levels of DNA-containing immune complexes.”

What the sources say

• Not checked yetcites [98] Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007). source

In the paper

“Specifically, HMGb1-bound DNA can form a complex with TLR9 and RAGe to induce pro-inflammatory cytokines98, which may be important for promoting inflammation in patients with systemic lupus erythematosus who have elevated circulating levels of DNA-containing immune complexes.”

What the sources say

• Not checked yetcites [98] Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007). source

In the paper

“The protein contains no obvious signalling domains90, although extracellular signal-regulated kinase (eRK) was shown to directly interact with the cytoplasmic tail of RAGe97.”

What the sources say

• Not checked yetcites [97] Ishihara, K., Tsutsumi, K., Kawane, S., Nakajima, M. & Kasaoka, T. The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site. FEBS Lett. 550, 107–113 (2003). source

In the paper

“Locally produced IL-1 then mediates neutrophil recruitment within the peritoneal cavity through IL-1R signalling and induction of CXCL1 production (FIG. 3).”

In the paper

“Although the clinical study was small, with only ten patients evaluated, all ten patients treated with anakinra had significant relief from symptoms108.”

What the sources say

• Not checked yetcites [108] So, A., De Smedt, T., Revaz, S. & Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 9, R28 (2007). source

In the paper

“This may provide one mechanism by which the host immune system can modulate responses to DAMPs and distinguish DAMPs from PAMPs107.”

What the sources say

• Not checked yetcites [107] Liu, Y., Chen, G. Y. & Zheng, P. CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns. Trends Immunol. 30, 557–561 (2009). source

In the paper

“Dying tumour cells release ATP and, indeed, the ability of dendritic cells to prime tumour-specific T cells required NLRP3 and P2RX7 (REF. 112).”

What the sources say

• Not checked yetcites [112] Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nature Med. 15, 1170–1178 (2009). source

In the paper

“A benefit for anakinra was also shown in a small, randomized trial of 70 patients with type 2 diabetes109.”

What the sources say

• Not checked yetcites [109] Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007). source

In the paper

“Although the clinical study was small, with only ten patients evaluated, all ten patients treated with anakinra had significant relief from symptoms108.”

What the sources say

• Not checked yetcites [108] So, A., De Smedt, T., Revaz, S. & Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 9, R28 (2007). source

In the paper

“Furthermore, chemotherapy-treated tumour cells injected into wild-type mice inhibited tumour development when the mice were rechallenged with tumour cells, but this effect was abrogated in NLRP3-deficient and P2RX7-deficient mice112, suggesting that NLRP3-mediated IL-1β production through the ATP–P2RX7 pathway is important for immune surveillance against tumours.”

What the sources say

• Not checked yetcites [112] Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nature Med. 15, 1170–1178 (2009). source

In the paper

“Furthermore, it was shown that TLR2 signalling by the endogenous extracellular matrix-derived proteoglycan versican can promote tumour metastasis34.”

What the sources say

• Not checked yetcites [34] Kim, S. et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009). source

In the paper

“TLR signalling is also implicated in the pathogenesis of atherosclerotic disease35–37.”

What the sources say

• Not checked yetcites [35] Mullick, A. E., Tobias, P. S. & Curtiss, L. K. Modulation of atherosclerosis in mice by Toll-like receptor 2. J. Clin. Invest. 115, 3149–3156 (2005). source
• Not checked yetcites [36] Michelsen, K. S. et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Natl Acad. Sci. USA 101, 10679–10684 (2004). source
• Not checked yetcites [37] Bjorkbacka, H. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature Med. 10, 416–421 (2004). source

In the paper

“It has also been shown that DAMP-specific receptors can negatively regulate inflammatory responses.”

What the sources say

• Not checked yetcites [106] Chen, G. Y., Tang, J., Zheng, P. & Liu, Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323, 1722–1725 (2009). source

In the paper

“Mice deficient in both TLR2 and TLR4 or in myeloid differentiation primary-response protein 88 (MYD88), an adaptor protein for TLR and IL-1R signalling, were protected against bleomycin-induced lung injury related to the generation of hyaluronan fragments, and administration of a hyaluronan-blocking peptide to wild-type mice provided similar, although incomplete, protection31.”

What the sources say

• Not checked yetcites [31] Jiang, D. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nature Med. 11, 1173–1179 (2005). This paper shows the dual role of TLRs in mediating sterile inflammation in response to hyaluronan fragments released during injury and in promoting tissue repair. source

In the paper

“Given the crucial role for IL-1 in sterile inflammatory responses, blockade of IL-1R has been tested as a therapeutic target for sterile inflammatory disorders in humans.”

What the sources say

• Not checked yetcites [43] Gabay, C., Lamacchia, C. & Palmer, G. IL-1 pathways in inflammation and human diseases. Nature Rev. Rheumatol. 6, 232–241 (2010). source
• Not checked yetcites [108] So, A., De Smedt, T., Revaz, S. & Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 9, R28 (2007). source
• Not checked yetcites [109] Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007). source

In the paper

“CD36 mediates heterodimer formation of TLR4 and TLR6 (REF. 104), and this co-receptor complex upregulates the production of chemokines and cytokines such as pro-IL-1β through the activation of NF-κb.”

What the sources say

• Not checked yetcites [104] Hoebe, K. et al. CD36 is a sensor of diacylglycerides. Nature 433, 523–527 (2005). source
• Not checked yetcites [105] Stewart, C. R. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunol. 11, 155–161 (2010). source

In the paper

“The clinical importance of this finding was suggested by the fact that, in early-stage breast cancer patients who were treated with chemotherapy, lower metastasis-free survival was associated with a TLR4 polymorphism that affects binding of HMGb1 to TLR4 (REF. 115).”

What the sources say

• Not checked yetcites [115] Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Med. 13, 1050–1059 (2007). This paper showed the importance of TLR4 signalling in response to DAMPs derived from tumour cell death after chemotherapy or radiation treatment during the induction of host immune responses that are important for inhibiting tumour growth. source