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Cited by 3,051Immune Response and InflammationInflammasome and immune disordersInflammation biomarkers and pathways

Sterile inflammation: sensing and reacting to damage

Open access
Chen, Grace Y., Nuñez, Gabriel·2010·Nature Reviews Immunology
DOI 10.1038/nri2873PMC PMC3114424
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Abstract

Over the past several decades, much has been revealed about the nature of the host innate immune response to microorganisms, with the identification of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the conserved microbial motifs sensed by these receptors. 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. The sterile inflammation that ensues either resolves the initial insult or leads to disease. Here, we review the triggers and receptor pathways that result in sterile inflammation and its impact on human health.

AI snapshot

Written from the paper’s full text.

TL;DR

Sterile inflammation is triggered when endogenous damage-associated molecular patterns (DAMPs) released by injured or necrotic cells activate the same pattern recognition receptors (PRRs) that sense microbial pathogens, notably TLRs, the NLRP3 and AIM2 inflammasomes, and C-type lectins. The review argues that IL-1 (particularly IL-1α and IL-1β) is a central mediator of these responses and a promising therapeutic target across gout, atherosclerosis, type 2 diabetes and cancer.

Key findings

  • DAMPs are endogenous molecules normally sequestered intracellularly (HMGB1, HSPs, ATP, uric acid) or generated by extracellular matrix degradation (hyaluronan, heparan sulphate, biglycan) that become immunostimulatory when released by necrosis; their relative importance and redundancy remain unresolved — uric acid depletion reduced neutrophil recruitment after acetaminophen-induced liver injury in two mouse models but had no effect in particulate-induced inflammation.
  • NLRP3 is activated by structurally diverse sterile stimuli (asbestos, silica, MSU and CPPD crystals, cholesterol crystals, β-amyloid fibrils); NLRP3-deficient mice showed decreased inflammation in gout, asbestosis and silicosis models, and LDL-receptor-deficient mice infused with NLRP3-deficient bone marrow had lower IL-1β, smaller atherosclerotic lesions and less neutrophilic infiltration.
  • Three proposed mechanisms of NLRP3 activation — ATP/P2RX7, lysosomal damage with cathepsin B, and ROS — are each supported only partially, with contradictory data (e.g., TXNIP-deficient macrophages showed impaired IL-1β in one study but no difference in another; p22phox- or Gp91phox-deficient macrophages had normal caspase 1 activation).
  • Therapeutic blockade of IL-1R with anakinra produced significant symptom relief in all ten evaluated gout patients who could not tolerate or respond to prior therapy, and improved glucose and reduced IL-6 and C-reactive protein in a randomized trial of 70 patients with type 2 diabetes; results in osteoarthritis and rheumatoid arthritis were not promising.

Methods

  • Narrative review (not a primary study) synthesizing the literature on sterile inflammation, its triggers, receptor pathways and disease implications.
  • Evidence drawn from in vitro and in vivo mouse models (including knockout and bone marrow chimera studies) and human clinical trials, organized around three proposed mechanisms: PRR activation by DAMPs, release of intracellular cytokines such as IL-1α, and direct activation via non-PRR receptors such as RAGE.
  • No new data, systematic search strategy or meta-analysis is reported.

Limitations

  • Stated by the paper: it is unclear whether DAMPs identified by in vitro cytokine induction (HSPs, S100 proteins, ATP) actually drive sterile inflammation in vivo; stimulatory activity of some purified DAMPs may reflect bacterial product contamination (HSPs and HMGB1 bind LPS); many DAMPs interact with several receptors, so the significance of individual interactions is unresolved; the relative importance and possible redundancy of individual DAMPs is unknown; the relevance of ROS and TXNIP in NLRP3 activation in vivo remains unclear and contested; whether RAGE and other non-PRRs have a primary or secondary role in human disease is unknown; and the clinical studies cited (10 gout patients; 70 type 2 diabetes patients) were small and not designed to determine optimal dosing, duration or long-term outcomes.
  • Evident from the text: the review is largely built on mouse models, and the authors repeatedly note that human relevance for NLRP3 in type 2 diabetes, RAGE in atherosclerosis and Alzheimer's disease, and CLEC4E/CLEC9A in sterile inflammation remains to be determined.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nri2873

Cites

127 of 127 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 207 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In ischaemia-reperfusion injury, restoration of blood flow causes further tissue destruction as a result of neutrophilic infiltration, enhanced production of ROS and inflammatory responses to necrotic cells.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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).

      Not checked in the free run.

  • Interpretationnone given

    PRRs can be activated by non-microbial signals, many of which are considered damage-associated molecular patterns (DAMPs).

    “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.”
    Quote in the paperSubstantial claim
  • Premisecitation

    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 destruction in gout and pseudogout.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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).

      Not checked in the free run.

  • Premisecitation

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

    “Chronic inhalation of sterile irritants, such as asbestos and silica, can lead to persistent activation of alveolar macrophages and result in pulmonary interstitial fibrosis1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Premisecitation

    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 vivo.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [34] Kim, S. et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 10
  • May combine two claims. 55

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Sterile inflammation either resolves the initial insult or leads to disease.

    “The sterile inflammation that ensues either resolves the initial insult or leads to disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Uric acid depletion does not completely eliminate acetaminophen-induced liver inflammation or the adjuvant activity of damaged cells, which may reflect residual uric acid following depletion or redundant activities by other DAMPs.

    “However, uric acid depletion does not completely eliminate acetaminophen-induced liver inflammation or the adjuvant activity of damaged cells, which may reflect residual uric acid following depletion or redundant activities by other DAMPs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Tlr2 and Tlr4 double-knockout mice exhibit impaired transepithelial recruitment of inflammatory cells and decreased survival in response to lung injury.

    “Tlr2 and Tlr4 double-knockout mice exhibit impaired transepithelial recruitment of inflammatory cells and decreased survival in response to lung injury31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Interpretationcitation

    In particulate-induced sterile inflammation, uric acid depletion had no effect, suggesting that uric acid may be a major pro-inflammatory DAMP specifically involved in cell death-related sterile inflammation.

    “by contrast, in particulate-induced sterile inflammation, uric acid depletion had no effect, suggesting that uric acid may be a major pro-inflammatory DAMP that is specifically involved in cell death-related sterile inflammation13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    TLR4 specifically mediates inflammatory responses to free fatty acids, which are elevated in obesity and are associated with insulin resistance.

    “TLR4, specifically, has been shown to mediate inflammatory responses to free fatty acids, which are elevated in obesity and are associated with insulin resistance38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TLR3 can sense endogenous RNA derived from necrotic neutrophils, which contributes to the inflammatory response elicited by necrosis in the bowel.

    “Similarly, TLR3 can sense endogenous RNA derived from necrotic neutrophils, which contributes to the inflammatory response elicited by necrosis in the bowel39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Cavassani, K. A. et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J. Exp. Med. 205, 2609–2621 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although IL-1α and IL-33 are not conventionally considered DAMPs, they can mediate sterile inflammatory responses.

    “Although these factors are not conventionally considered as DAMPs, they can mediate sterile inflammatory responses (see below).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Understanding the mechanisms of sterile inflammation is important for devising treatment strategies against various human diseases.

    “Thus, understanding the mechanisms of sterile inflammation is important for devising treatment strategies against various human diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Three mechanisms by which sterile endogenous stimuli trigger inflammation are: activation of PRRs by mechanisms similar to microorganisms and PAMPs; release of intracellular cytokines and chemokines such as IL-1α that activate common pathways downstream of PRRs; and direct activation by receptors not typically associated with microbial recognition.

    “based on our current understanding, we propose three, not necessarily mutually exclusive, mechanisms by which sterile endogenous stimuli trigger inflammation: activation of PRRs by mechanisms similar to those used by microorganisms and PAMPs; release of intracellular cytokines and chemokines, such as IL-1α, that activate common pathways downstream of PRRs; and direct activation by receptors that”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The three proposed mechanisms by which sterile endogenous stimuli trigger inflammation are not necessarily mutually exclusive.

  • May combine two claims.

    Premisecitation

    PRRs also recognize non-infectious material that can cause tissue damage and endogenous molecules released during cellular injury.

    “It is now evident that PRRs also recognize non-infectious material that can cause tissue damage and endogenous molecules that are released during cellular injury (TABLE 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites TABLE 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immune cell infiltration in the absence of microorganisms is characteristic of tumours, and these cells can influence the growth and progression of cancer.

    “Finally, immune cell infiltration in the absence of microorganisms is also characteristic of tumours, and these cells can influence the growth and progression of cancer6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DAMPs have been identified by their ability to induce inflammatory responses in vitro and/or in vivo when purified and by the observed reduction in inflammation when they are selectively depleted.

    “DAMPs have been identified by their ability to induce inflammatory responses in vitro and/orin vivo when purified and by the observed reduction in inflammation when they are selectively depleted17.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nature Rev. Immunol. 8, 279–289 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The anti-diabetic drug glyburide has been shown to block glucose-mediated secretion of IL-1β by mouse pancreatic islets, as well as IL-1β production by macrophages in response to IAPP, and NLRP3-deficient mice were more glucose tolerant than wild-type mice.

    “Interestingly, the anti-diabetic drug glyburide (Glibenclamide; Roche/Sanofi-Aventis) has been shown to block glucose-mediated secretion of IL-1β by mouse pancreatic islets62, as well as IL-1β production by macrophages in response to IAPP61, and NLRP3-deficient mice were more glucose tolerant than wild-type mice62.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLRP3-dependent caspase 1 activation was associated with destabilization of the lysosomal membrane and activation of lysosomal proteases (specifically, cathepsin B).

    “Importantly, NLRP3-dependent caspase 1 activation was associated with destabilization of the lysosomal membrane and activation of lysosomal proteases (specifically, cathepsin b)44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Compared with wild-type mice, IL-1R-deficient mice had decreased neutrophilic infiltration and inflammation in the liver after acetaminophen-induced liver injury and in the lungs after exposure to silica.

    “Compared with wild-type mice, IL-1R-deficient mice had decreased neutrophilic infiltration and inflammation in the liver after acetaminophen-induced liver injury22 and in the lungs after exposure to silica44.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    NLRP3 signalling involves at least two steps: first, PRR- or cytokine-dependent transcriptional upregulation of NLRP3; second, activation of the NLRP3 inflammasome, which leads to IL-1β production.

    “NLRP3 signalling has been shown to involve at least two steps, the first involving PRR- or cytokine-dependent transcriptional upregulation of NLRP3 and the second involving activation of the NLRP3 inflammasome, which leads to IL-1β production53,54 (BOX 4).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Bauernfeind, F. G. et al. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009). source

      Not checked in the free run.

    • cites [54] Franchi, L., Eigenbrod, T. & Nunez, G. Cutting edge: TNF-α mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J. Immunol. 183, 792–796 (2009). References 53 and 54 provide evidence that the first signal, or priming event, necessary for activation of the NLRP3 inflammasome involves upregulation of NLRP3 expression by NF-κB through the action of TLRs or pro-inflammatory cytokines such as TNF. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    TLRs seem to function redundantly with other signalling pathways, so the contribution of TLRs to the overall sterile inflammatory response remains unclear.

    “Furthermore, TLRs seem to function redundantly with other signalling pathways, so the contribution of TLRs to the overall sterile inflammatory response remains unclear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The amounts of ATP necessary for NLRP3-mediated caspase 1 activation to be detected in macrophages in vitro are greater than physiological concentrations, therefore the relevance of this pathway in vivo is uncertain.

    “However, the amounts of ATP necessary for NLRP3-mediated caspase 1 activation to be detected in macrophages in vitro are greater than physiological concentrations63 and, therefore, the relevance of this pathway in vivo is uncertain.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] el-Moatassim, C. & Dubyak, G. R. A novel pathway for the activation of phospholipase D by P2z purinergic receptors in BAC1.2F5 macrophages. J. Biol. Chem. 267, 23664–23673 (1992). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated levels of IL-1β are observed in pancreatic islet cells from patients with type 2 diabetes, which is increasingly being recognized as having a strong inflammatory component.

    “elevated levels of IL-1β are also observed in the pancreatic islet cells from patients with type 2 diabetes46, which is increasingly being recognized as having a strong inflammatory component47.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Boni-Schnetzler, M. et al. Increased interleukin (IL)-1β messenger ribonucleic acid expression in β-cells of individuals with type 2 diabetes and regulation of IL-1β in human islets by glucose and autostimulation. J. Clin. Endocrinol. Metab. 93, 4065–4074 (2008). source

      Not checked in the free run.

    • cites [47] Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    NLRP3 senses intracellular K+ depletion, which may act as a surrogate marker of cellular injury.

    “Thus, it has been suggested that NLRP3 senses intracellular K + depletion, which may act as a surrogate marker of cellular injury that is sensed by NLRP3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    IL-1β secretion was only partially dependent on P2RX7, suggesting that the release of ATP may be only one mechanism by which necrotic cells can activate NLRP3.

    “However, IL-1β secretion was only partially dependent on P2RX7, suggesting that the release of ATP may be only one mechanism by which necrotic cells can activate NLRP3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATP binds to purinergic receptor P2X7 (P2RX7), which leads to the opening of an ATP-gated cation channel that induces K+ efflux and the formation of a large pore mediated by the hemichannel protein pannexin 1.

    “ATP binds to purinergic receptor P2X7 (P2RX7), which leads to the opening of an ATP-gated cation channel that induces K + efflux and the formation of a large pore mediated by the hemichannel protein pannexin 1 (REFS 64,65).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Pelegrin, P. & Surprenant, A. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J. 25, 5071–5082 (2006). source

      Not checked in the free run.

    • cites [65] Locovei, S., Wang, J. & Dahl, G. Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium. FEBS Lett. 580, 239–244 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In atherosclerosis, engulfment of cholesterol by macrophages leads to IL-1β production, which can stimulate production of platelet-derived growth factor, promotion of smooth muscle cell and fibroblast proliferation, arterial wall thickening and plaque formation.

    “In atherosclerosis, engulfment of cholesterol by macrophages leads to IL-1β production, which can stimulate the production of platelet-derived growth factor, promotion of smooth muscle cell and fibroblast proliferation, arterial wall thickening and plaque formation5,45.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Ross, R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999). source

      Not checked in the free run.

    • cites [45] Raines, E. W., Dower, S. K. & Ross, R. Interleukin-1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA. Science 243, 393–396 (1989). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Endogenous stimuli can induce a sterile inflammatory response through TLRs, although the precise molecules that engage TLRs remain poorly defined.

    “Collectively, the evidence suggests that endogenous stimuli can induce a sterile inflammatory response through TLRs, although the precise molecules that engage TLRs remain poorly defined.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IL-1β is a potent pro-inflammatory cytokine produced mainly by macrophages and has many biological functions important in sterile inflammation, such as upregulation of adhesion molecules on endothelial cells for recruitment of neutrophils and monocytes and induction of additional pro-inflammatory mediators.

    “IL-1β is a potent pro-inflammatory cytokine that is produced mainly by macrophages and has many biological functions that are important in sterile inflammation, such as the upregulation of those adhesion molecules on endothelial cells that are important for the recruitment of neutrophils and monocytes42 and for the induction of additional pro-inflammatory mediators43.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Wang, X., Feuerstein, G. Z., Gu, J. L., Lysko, P. G. & Yue, T. L. Interleukin-1β induces expression of adhesion molecules in human vascular smooth muscle cells and enhances adhesion of leukocytes to smooth muscle cells. Atherosclerosis 115, 89–98 (1995). source

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    LDL receptor-deficient mice prone to developing atherosclerotic lesions had lower IL-1β levels, smaller atherosclerotic lesions and less neutrophilic infiltration than wild-type mice when lethally irradiated and infused with NLRP3-deficient bone marrow.

    “Low-density lipoprotein (LDL) receptor-deficient mice, which are prone to developing atherosclerotic lesions, had lower IL-1β levels, smaller atherosclerotic lesions and less neutrophilic infiltration than wild-type mice when lethally irradiated and infused with NLRP3-deficient bone marrow59.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-1, which includes both IL-1α and IL-1β, is a key mediator of sterile inflammation that acts through the IL-1 receptor (IL-1R).

    “IL-1, which includes both IL-1α and IL-1β, is a key mediator of sterile inflammation that acts through the IL-1 receptor (IL-1R)22,41.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lysosomal damage can occur during cellular injury and necrosis, and has also been associated with other sterile activators of NLRP3, such as cholesterol and silica crystals.

    “Lysosomal damage can occur during cellular injury and necrosis, and has also been associated with other sterile activators of NLRP3, such as cholesterol59 and silica crystals44.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010). source

      Not checked in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    NLRP3-deficient mice were less susceptible to renal ischaemia-reperfusion injuries induced by bilateral renal artery ligation and to acetaminophen-induced hepatotoxicity.

    “NLRP3-deficient mice were also less susceptible to renal ischaemia–reperfusion injuries induced by bilateral renal artery ligation and to acetaminophen-induced hepatotoxicity40,60.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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).

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In general, the ligands of CLRs are unknown.

    “In general, the ligands of these CLRs are unknown70.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Geijtenbeek, T. B. & Gringhuis, S. I. Signalling through C-type lectin receptors: shaping immune responses. Nature Rev. Immunol. 9, 465–479 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The CLR class of PRRs contains a carbohydrate-binding domain that recognizes carbohydrates on viruses, bacteria and fungi.

    “This class of PRRs contains a carbohydrate-binding domain that recognizes carbohydrates on viruses, bacteria and fungi.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Using a model of peritonitis triggered by necrotic cells, IL-1α was shown to be important for the recruitment of neutrophils, which was caspase 1 independent, and this response was impaired in mice lacking IL-1R expression by non-myeloid cells.

    “Using a model of peritonitis triggered by necrotic cells, IL-1α was shown to be important for the recruitment of neutrophils, which was caspase 1 independent, and this response was impaired in mice lacking IL-1R expression by non-myeloid cells22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    CLRs are an increasingly recognized category of PRRs that are important in host defence.

    “CLRs are an increasingly recognized category of PRRs that are important in host defence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    C-type lectin 4e (CLEC4e; also known as MINCLE) can detect the DAMP spliceosome-associated protein 130 (SAP130), which is a component of a small nuclear ribonucleo protein that can be released by necrotic but not apoptotic cells, resulting in upregulation of pro-inflammatory mediators such as CXCL2 and in neutrophil recruitment.

    “In particular, C-type lectin 4e (CLeC4e; also known as MINCLe) can detect the DAMP spliceosome-associated protein 130 (SAP130), which is a component of a small nuclear ribonucleo protein that can be released by necrotic but not apoptotic cells, resulting in upregulation of pro-inflammatory mediators such as CXC-chemokine ligand 2 (CXCL2) and in neutrophil recruitment73.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Cambi, A. & Figdor, C. Necrosis: C-type lectins sense cell death. Curr. Biol. 19, R375–R378 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CLEC9A may be involved in regulating sterile immune responses, although the specific ligand recognized in this case is still unknown.

    “Therefore, it may be involved in regulating sterile immune responses, although the specific ligand recognized in this case is still unknown73,75.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] Cambi, A. & Figdor, C. Necrosis: C-type lectins sense cell death. Curr. Biol. 19, R375–R378 (2009). source

      Not checked in the free run.

    • cites [75] Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899–903 (2009). This paper showed a role for CLEC9A in regulating immune responses to sterile cell death, specifically through the cross-presentation of dead cell-associated antigens. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Silica, asbestos and ATP have all been associated with ROS production, and ROS inhibition in vitro resulted in impairment of caspase 1 activation and IL-1β production by these stimuli.

    “Silica58,68, asbestos57 and ATP69 have all been associated with ROS production, and ROS inhibition in vitro resulted in impairment of caspase 1 activation and IL-1β production by these stimuli57,58,69.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [68] Fubini, B. & Hubbard, A. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Radic. Biol. Med. 34, 1507–1516 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Artificial lysosomal rupture alone can activate NLRP3, and pharmacological inhibition or genetic depletion of cathepsin B results in inhibition of caspase 1 activation, although this inhibition was only partial.

    “evidence to support this are the observations that artificial lysosomal rupture alone can activate NLRP3 and that pharmacological inhibition or genetic depletion of cathepsin b results in inhibition of caspase 1 activation, although this inhibition was only partial44,56,59.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [59] Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    There is still controversy regarding the roles of the individual model pathways for NLRP3 activation, and it remains to be determined whether there is a common mechanism by which numerous heterogeneous stimuli converge on NLRP3.

    “Collectively, there is still controversy regarding the roles of the individual model pathways for NLRP3 activation, and it remains to be determined whether there is a common mechanism by which numerous heterogeneous stimuli converge on NLRP3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    When cells die by necrosis, the precursor form of IL-1α is released, leading to activation of its cognate receptor and rapid recruitment of inflammatory cells into the surrounding injured tissue.

    “when cells die by necrosis, such as during injury, this precursor form of IL-1α is released, leading to activation of its cognate receptor and rapid recruitment of inflammatory cells into the surrounding injured tissue22,78.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

      Not checked in the free run.

    • cites [78] Cohen, I. et al. Differential release of chromatin-bound IL-1α discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc. Natl Acad. Sci. USA 107, 2574–2579 (2010). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Divergent upstream danger signals sensed by NLRP3 may converge on lysosomal damage and cathepsin B activation.

    “Therefore, it is possible that divergent upstream danger signals that are sensed by NLRP3 may converge on lysosomal damage and cathepsin b activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Unlike its related family members IL-1β and IL-18, IL-1α is synthesized as a biologically active cytokine in its full-length precursor form and does not require processing for signalling through IL-1R.

    “Unlike its related family members IL-1β and IL-18, IL-1α is synthesized as a biologically active cytokine in its full-length precursor form and does not require processing for signalling through IL-1R78,79.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Cohen, I. et al. Differential release of chromatin-bound IL-1α discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc. Natl Acad. Sci. USA 107, 2574–2579 (2010). source

      Not checked in the free run.

    • cites [79] Dinarello, C. A. IL-1: discoveries, controversies and future directions. Eur. J. Immunol. 40, 599–606 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TXNIP-deficient mice had impaired IL-1β production and neutrophil influx after intraperitoneal injection of MSU crystals, and TXNIP-deficient macrophages had decreased IL-1β production in response to a range of known NLRP3 activators, including MSU crystals, silica, and ATP.

    “In this study, TXNIP-deficient mice had impaired IL-1β production and neutrophil influx after intraperitoneal injection of MSU crystals, and TXNIP-deficient macrophages had decreased IL-1β production in response to a range of known NLRP3 activators, including MSU crystals, silica, and ATP62.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This is in contrast with apoptotic cells, in which IL-1α is sequestered intracellularly, or with intact cells, in which the secretion of mature IL-1α is partially dependent on caspase 1 activity.

    “This is in contrast with apoptotic cells, in which IL-1α is sequestered intracellularly78, or with intact cells, in which the secretion of mature IL-1α is partially dependent on caspase 1 activity80–82.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [78] Cohen, I. et al. Differential release of chromatin-bound IL-1α discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc. Natl Acad. Sci. USA 107, 2574–2579 (2010). source

      Not checked in the free run.

    • cites [80] Li, P. et al. Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock. Cell 80, 401–411 (1995). source

      Not checked in the free run.

    • cites [81] Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1β converting enzyme. Science 267, 2000–2003 (1995). source

      Not checked in the free run.

    • cites [82] Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CLEC9A has been shown to recognize necrotic cells and induce the cross-presentation of dead cell-associated antigens to CD8+ T cells.

    “CLeC9A has been shown to recognize necrotic cells and induce the cross-presentation of dead cell-associated antigens to CD8+ T cells.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] Cambi, A. & Figdor, C. Necrosis: C-type lectins sense cell death. Curr. Biol. 19, R375–R378 (2009). source

      Not checked in the free run.

    • cites [75] Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899–903 (2009). This paper showed a role for CLEC9A in regulating immune responses to sterile cell death, specifically through the cross-presentation of dead cell-associated antigens. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AGEs can accumulate under conditions of high oxidant stress and are found at elevated levels in chronic inflammatory disease states such as type 1 diabetes.

    “These products can accumulate under conditions of high oxidant stress and are found at elevated levels in chronic inflammatory disease states such as type 1 diabetes92.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Apoe-/-Rage-/- mice exhibited reduced atherosclerosis, shown by reduced atherosclerotic plaque formation and reduced production of pro-inflammatory mediators within the aorta.

    “Apoe–/–Rage–/– mice also exhibited a reduction in atherosclerosis101, as shown by a reduction in both atherosclerotic plaque formation and production of pro-inflammatory mediators within the aorta.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Harja, E. et al. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE−/− mice. J. Clin. Invest. 118, 183–194 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    β-amyloid accumulation is pathogenic in Alzheimer's disease.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Yan, S. D. et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease. Nature 382, 685–691 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The release of IL-1α from certain cells, such as dendritic cells, contributes to sterile inflammation, but macrophages seem to be the primary sentinel cells that mediate the sensing of necrotic cells through the production of mature IL-1α and IL-1β.

    “Thus, the release of IL-1α from certain cells, such as dendritic cells, contributes to sterile inflammation, but macrophages seem to be the primary sentinel cells that mediate the sensing of necrotic cells through the production of mature IL-1α and IL-1β41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The precursor forms of IL-1α and IL-33 (both of which are biologically active) are preferentially released during necrosis to alert the immune system to cell damage, leading to the initiation of the healing response.

    “Collectively, the evidence suggests that the precursor forms of IL-1α and IL-33 (both of which are biologically active) are preferentially released during necrosis to alert the immune system to cell damage, leading to the initiation of the healing response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The precursor form of IL-1α that is released by necrotic cells contributes to the initial neutrophilic response, but resident macrophages are the main source of mature IL-1α and IL-1β, which are needed for cell death-induced sterile inflammation.

    “These studies suggest that the precursor form of IL-1α that is released by necrotic cells contributes to the initial neutrophilic response, but resident macrophages are the main source of mature IL-1α and IL-1β, which are needed for cell death-induced sterile inflammation (FIG. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    IL-33, which is expressed at high levels by endothelial cells and some epithelial cells, is expected to be active when it is released during necrosis, but not apoptosis, which is associated with executioner caspase activation.

    “Thus, IL-33, which is expressed at high levels by endothelial cells and some epithelial cells, is expected to be active when it is released during necrosis, but not apoptosis, which is associated with executioner caspase activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CD44 physically interacts with TLR4 in vitro and functions as an accessory molecule for TLR4 signalling in response to hyaluronan.

    “How CD44 signalling contributes to sterile inflammation is unclear, but it has been shown to physically interact with TLR4 in vitro and function as an accessory molecule for TLR4 signalling in response to hyaluronan102,103.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [102] Jiang, D., Liang, J. & Noble, P. W. Hyaluronan in tissue injury and repair. Annu. Rev. Cell Dev. Biol. 23, 435–461 (2007). source

      Not checked in the free run.

    • cites [103] Taylor, K. R. et al. Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2. J. Biol. Chem. 282, 18265–18275 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HMGB1 and S100 family members are released during cellular stress and necrotic cell death.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD24-mediated inhibition was associated with increased pro-inflammatory cytokine production by HMGB1 and decreased survival following acetaminophen-induced liver injury.

    “CD24-mediated inhibition was associated with increased pro-inflammatory cytokine production by HMGb1 and decreased survival following acetaminophen-induced liver injury106.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the type 2 diabetes trial, those treated with anakinra had improved glucose levels and reduced systemic inflammation, as suggested by lower circulating levels of inflammatory markers such as IL-6 and C-reactive protein.

    “Those treated with anakinra had improved glucose levels and reduced systemic inflammation, as suggested by lower circulating levels of inflammatory markers, such as IL-6 and C-reactive protein.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD36 is a scavenger receptor that binds oxidized LDL and β-amyloid.

    “Similarly, CD36 is a scavenger receptor that binds oxidized LDL and β-amyloid, which are associated with sterile inflammation related to atherosclerosis and Alzheimer's disease, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Hoebe, K. et al. CD36 is a sensor of diacylglycerides. Nature 433, 523–527 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice deficient in TLR2 and TLR4 expression had increased mortality in response to hypoxia-induced lung injury, associated with decreased integrity of the lung epithelium.

    “Indeed, mice deficient in TLR2 and TLR4 expression had increased mortality in response to hypoxia-induced lung injury, which was associated with decreased integrity of the lung epithelium31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    TLR4 signalling is important for dendritic cell-mediated cross-presentation of tumour antigens from dying, chemotherapy-treated tumour cells and involves HMGB1 release from the dying cells.

    “TLR4 signalling was found to be important for dendritic cell-mediated cross-presentation of tumour antigens from dying, chemotherapy-treated tumour cells and involved HMGb1 release from the dying cells115.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 mice.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The clinical study of anakinra in type 2 diabetes was small and was not designed to determine optimal dosing, duration of use or long-term outcomes in disease control.

    “However, the clinical study was still small and was not designed to determine optimal dosing, duration of use or long-term outcomes in disease control.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Oxidized LDL and β-amyloid are associated with sterile inflammation related to atherosclerosis and Alzheimer's disease, respectively.

    “Similarly, CD36 is a scavenger receptor that binds oxidized LDL and β-amyloid, which are associated with sterile inflammation related to atherosclerosis and Alzheimer's disease, respectively.”
    Quote in the paperNot a substantial claim
61 of 61

  • The paper relies on this without support.

    Sterile inflammation is marked by the recruitment of neutrophils and macrophages and the production of pro-inflammatory cytokines and chemokines, notably tumour necrosis factor (TNF) and interleukin-1 (IL-1).

    “Similar to microbially induced inflammation, sterile inflammation is marked by the recruitment of neutrophils and macrophages and the production of pro-inflammatory cytokines and chemokines, notably tumour necrosis factor (TNF) and interleukin-1 (IL-1).”

  • The paper relies on this without support.

    DAMPs are endogenous factors that are normally sequestered intracellularly and are therefore hidden from recognition by the immune system under normal physiological conditions.

    “A common feature of DAMPs is that they are endogenous factors that are normally sequestered intracellularly and are therefore hidden from recognition by the immune system under normal physiological conditions.”

  • The paper relies on this without support.

    Under conditions of cellular stress or injury, DAMPs can be released into the extracellular environment by dying cells and trigger inflammation under sterile conditions.

    “However, under conditions of cellular stress or injury, these molecules can then be released into the extracellular environment by dying cells and trigger inflammation under sterile conditions.”

  • The paper relies on this without support.

    The type of cell death affects its immunogenicity and its ability to release immunostimulatory DAMPs.

    “The type of cell death notably affects its immunogenicity and ability to release immunostimulatory DAMPs.”

  • The paper relies on this without support.

    Secretion of IL-1β by inflammatory cells is largely dependent on a multiprotein complex termed the inflammasome, of which the hallmark activity is the activation of caspase 1.

    “The secretion of IL-1β by inflammatory cells is largely dependent on a multiprotein complex termed the inflammasome, of which the hallmark activity is the activation of caspase 1.”

  • The authors state this as an assumption.

    The three proposed mechanisms by which sterile endogenous stimuli trigger inflammation are not necessarily mutually exclusive.

    “based on our current understanding, we propose three, not necessarily mutually exclusive, mechanisms by which sterile endogenous stimuli trigger inflammation:”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • TLRs are activated by a wide array of endogenous molecules released from self-cells following tissue damage (DAMPs) such as hyaluronic acid and molecules derived from necrotic and apoptotic cells including nucleic acids.

    “In addition, TLRs are activated by a wide array of endogenous molecules released from self-cells following tissue damage (known as damage-associated molecular pattern, DAMP) such as hyaluronic acid and molecules derived from necrotic and apoptotic cells including nucleic acids [42].”

    From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [42]

    The section on TLR recognition of endogenous DAMPs reports activation by molecules from necrotic cells or the extracellular matrix, explicitly including endogenous nucleic acids and hyaluronan. It also describes TLR sensing of RNA and DNA from necrotic cells. The cited passages do not establish the claim's additional attribution to molecules derived from apoptotic cells. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Stressor exposure may also stimulate sterile inflammation in the brain, or neuroinflammation.

    “these current studies suggest that stressor exposure may also stimulate sterile inflammation in the brain, or neuroinflammation (Chen and Nunez, 2010).”

    From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Chen and Nunez, 2010

  • In peritoneal dialysis and hemodialysis patients, CBT-I improved sleep quality compared with a sleep hygiene education intervention, which was paralleled by a decrease of serum levels of inflammatory markers, including IL-1, CRP, and IL-18.

    “In peritoneal dialysis and hemodialysis patients, CBT-I improved sleep quality compared with a sleep hygiene education intervention, which was paralleled by a decrease of serum levels of inflammatory markers, including IL-1 (102), CRP, and IL-18 (101).”

    From The Sleep-Immune Crosstalk in Health and Disease (2019) · cites this paper as [101]

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Related

Authors
Chen, G. Y., & Nuñez, G.
Affiliations
University of Michigan (US)
ORCID
Chen, Grace Y.
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2010-11-19
Volume
10
Issue
12
Pages
826-837
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/nri2873
PMC
PMC3114424
OpenAlex
W2042851093
Semantic Scholar
ecc0e7ccec243d3412e5a1ad96c82cf4b1c3a3df
Cited by
3,051
References
128
Citations by year
2026: 150 · 2025: 141 · 2024: 186 · 2023: 199 · 2022: 224 · 2021: 245 · 2020: 248 · 2019: 190 · 2018: 231 · 2017: 209 · 2016: 198 · 2015: 193 · 2014: 207 · 2013: 164 · 2012: 148
FWCI
10.93
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Amgen
  • National Cancer Institute (CA133185, K08CA133185)
  • National Institute of Allergy and Infectious Diseases (R01AI063331, AI06331)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 61707, DK091191, R01DK061707, R01DK091191)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 051790, R01AR059688, AR059688)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords
sterile inflammation, damage-associated molecular patterns, pattern recognition receptors, pathogen-associated molecular patterns, innate immune response, inflammation resolution, inflammatory diseases
MeSH terms
Animals, Diabetes Mellitus, Type 2, Humans, Immunity, Innate, Inflammation, Signal Transduction, Reperfusion Injury, Cytokines, Reactive Oxygen Species, Inflammation Mediators, Receptors, Pattern Recognition, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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