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Cited by 1,341Atherosclerosis and Cardiovascular DiseasesFatty Acid Research and HealthCholesterol and Lipid Metabolism

Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities

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Bäck, Magnus, Yurdagul, Arif, Tabas, Ira, Öörni, Katariina, Kovanen, Petri T.·2019·Nature Reviews Cardiology
DOI 10.1038/s41569-019-0169-2PMC PMC6727648
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Abstract

Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.

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  • Premisecitation

    Macrophage uptake and lysosomal degradation of modified pro-atherogenic lipoproteins lowers the extracellular concentration of these lipoproteins.

    “uptake and ensuing lysosomal hydrolytic degradation of these pro-atherogenic lipoproteins by macrophages lowers the concentration of the pro-inflammatory lipoproteins in the extracellular fluid21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Premisenone given

    Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules.

    “Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    A low resolvin D1 to leukotriene B4 ratio in saliva can predict carotid intimal thickness in humans.

    “a low resolvin D1 (RvD1):leukotriene B4 ratio in saliva can predict carotid intimal thickness in humans37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Premisecitation

    Blocking LDL retention with antibodies against sulfated glycosaminoglycans of proteoglycans decreases LDL modification and atherosclerosis.

    “blocking of LDL retention with antibodies generated against the sulfated glycosamino-glycans of proteoglycans decreases LDL modification and atherosclerosis48.”
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  • Premisecitation

    Interaction of apoB-containing lipoproteins with intimal extracellular proteoglycans inhibits their movement, producing higher subendothelial concentrations in the intima than in other tissues.

    “the interaction of apoB-containing lipoproteins (the non-HDL lipoproteins) with intimal extracellular proteoglycans (referred to as retention)1,43,44 inhibits the movement of the lipoproteins, thereby resulting in much higher subendothelial concentrations of these lipoproteins in the intima than in any other tissue45.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    Premisecitation

    In transgenic mice expressing a single-chain variable fragment of an oxPL-recognizing natural antibody, macrophages showed decreased oxLDL uptake, decreased oxPL-induced inflammation, and reduced atherosclerosis compared with controls.

    “macrophages of transgenic mice expressing a single-chain variable fragment of an oxPL-recognizing natural antibody showed decreased uptake of oxLDL compared with macrophages from control mice51. Moreover, these mice had decreased oxPL-induced inflammation and reduced atherosclerosis compared with the control mice.”
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    • cites [51] Que, X. et al. Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice. Nature 558, 301–306 (2018). source

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    Premisecitation

    Pro-resolving mediators block inflammatory cell influx, promote egress of inflammatory cells, modulate pro-inflammatory T cell responses, and promote clearance of pathogens and dead cells, limiting tissue damage and enabling repair.

    “By activating cell-surface receptors, pro-resolving mediators block inflammatory cell influx and promote the egress of inflammatory cells, modulate pro-inflammatory T cell responses and promote clearance of both pathogens and dead cells (efferocytosis), with all these functions serving to limit tissue damage and to enable the repair of injured tissue29,30.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisenone given

    Intimal infiltration and modification of plasma lipoproteins and their macrophage uptake with foam cell formation initiate atherosclerotic lesions, while defective efferocytosis sustains progression.

    “Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression.”
    Quote in the paperSubstantial claim

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    Premisecitation

    OxPLs in oxLDL activate endothelial cells and control endothelial barrier permeability, and oxPLs released from dying cells are captured by CD14 on dendritic cells, causing inflammasome-dependent phagocyte hyperactivation.

    “the oxPLs present in oxLDL activate endothelial cells and control the endothelial barrier permeability52,53, and oxPLs released from dying cells are captured by the CD14 receptor on dendritic cells, with ensuing inflammasome-dependent phagocyte hyperactivation54.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [52] Watson, A. D. et al. Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo. J. Biol. Chem. 272, 13597–13607 (1997). source

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    Premisecitation

    Many chronic inflammatory diseases, including advanced atherosclerosis, are characterized by an imbalance between pro-resolving and pro-inflammatory mediators such as leukotrienes, leading to defective resolution, tissue injury, and DAMP-mediated inflammation.

    “Many chronic inflammatory diseases, including advanced atherosclerosis, are characterized by an imbalance between pro-resolving and pro-inflammatory mediators, such as leukotrienes, leading to defective resolution of inflammation, tissue injury and damage-associated molecular pattern (DAMP)-mediated inflammation31–33.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] Tabas, I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat. Rev. Immunol. 10, 36–46 (2010). source

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    Premisecitation

    Continual hydrolysis and re-esterification of droplet cholesterol is a futile cycle that wastes ATP and contributes to premature death of foam cells in poorly oxygenated atherosclerotic regions.

    “the continual hydrolysis and re-esterification of droplet cholesterol constitutes a futile cycle that wastes ATP and thereby contributes to the premature death of the foam cells in poorly oxygenated regions of atherosclerotic lesions24,25.”
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    Premisecitation

    Lysosomal hydrolysis of cholesteryl ester generates unesterified cholesterol, which is re-esterified in the cytoplasm into cholesteryl ester droplets, leading to foam cell formation.

    “the lysosomal hydrolysis of cholesteryl ester generates unesterified cholesterol molecules, which then exit the lysosomes and become re-esterified in the cytoplasm, with ensuing formation of cytoplasmic cholesteryl ester droplets that leads to foam cell formation, a hallmark of atherosclerosis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    Multiply modified, aggregated apoB-containing lipoproteins are found in atherosclerotic lesions and embed cholesterol crystals.

    “Multiply modified, aggregated, apoB-containing lipoproteins are found in atherosclerotic lesions, and these particles were shown to embed cholesterol crystals56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Lehti, S. et al. Extracellular lipid accumulates in human carotid arteries as distinct three-dimensional structures with proinflammatory properties. Am. J. Pathol. 188, 525–538 (2018). source

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    Premisecitation

    Human atherosclerotic lesions show increased expression of major NLRP3 components, and inhibition of the NLRP3 inflammasome reduces atherosclerosis in Apoe−/− mice.

    “Human atherosclerotic lesions show increased expression of the major components of NLRP3 (REF 61), and inhibition of the NLRP3 inflammasome reduces atherosclerosis in Apoe−/− mice62.”
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    • cites [61] Rajamäki, K. et al. P38δ MAPK: a novel regulator of NLRP3 inflammasome activation with increased expression in coronary atherogenesis. Arterioscler. Thromb. Vasc. Biol. 36, 1937–1946 (2016). source

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    • cites [62] van der Heijden, T. et al. NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipoprotein E-deficient mice - brief report. Arterioscler. Thromb. Vasc. Biol. 37, 1457–1461 (2017). source

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    Premisecitation

    ALX/FPR2 is activated by agonists with partly opposing effects: SPMs and annexin-derived peptides promote M2-like macrophage polarization and pro-resolving signalling, while acute phase, bacterial, or mitochondrial peptides elicit pro-inflammatory signalling.

    “whereas SPMs and annexin-derived peptides promote M2-like macrophage polarization and pro-resolving signalling through ALX/FPR2, the same receptor elicits pro-inflammatory signalling when activated by acute phase, bacterial or mitochondrial peptides103.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Bäck, M. et al. Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR review 7. Br. J. Pharmacol. 171, 3551–3574 (2014). source

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    Premisecitation

    ChemR23 levels become elevated during monocyte-to-macrophage differentiation in vitro, and RvE1 signalling via ChemR23 increases phagocytosis in human macrophages in vitro.

    “The levels of the RvE1 receptor ChemR23 become elevated during the differentiation of monocytes to macrophages in vitro114, and signalling of RvE1 via ChemR23 increases phagocytosis in human macrophages in vitro115,116.”
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    • cites [114] Herova, M., Schmid, M., Gemperle, C. & Hersberger, M. ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages. J. Immunol. 194, 2330–2337 (2015). source

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    Premisecitation

    ALX/FPR2 and ChemR23 are expressed in human aortic, coronary, and carotid atherosclerotic lesions, indicating that their pro-resolving ligands act locally within the vascular wall.

    “These receptors are expressed in human aortic, coronary and carotid atherosclerotic lesions104–106, indicating that their pro-resolving ligands exert local effects within the vascular wall (TABLE 1).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [104] Petri, M. H. et al. The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability. Cardiovasc. Res. 105, 65–74 (2015). source

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    • cites [105] Laguna-Fernandez, A. et al. ERV1/ChemR23 signaling protects from atherosclerosis by modifying oxLDL uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018). source

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    • cites [106] Kostopoulos, C. G., Spiroglou, S. G., Varakis, J. N., Apostolakis, E. & Papadaki, H. H. Chemerin and CMKLR1 expression in human arteries and periadventitial fat: a possible role for local chemerin in atherosclerosis? BMC Cardiovasc. Disord. 14, 56 (2014). source

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    Premisecitation

    RvD2 inhibited secretion of mature IL-1β by mouse macrophages in vitro and facilitated inflammation resolution in a mouse peritonitis model.

    “RvD2 potently inhibited the secretion of mature IL-1β by mouse macrophages in vitro, and by the same mechanism also facilitated the inflammation resolution process in a mouse model of peritonitis, with self-resolution and limited inflammation in vivo67.”
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    • cites [67] Lopategi, A. et al. Frontline science: specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. J. Leukoc. Biol. 105, 25–36 (2018). source

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    Premisecitation

    Murine macrophages derived from ChemR23-deficient mice have increased production of pro-inflammatory cytokines and lack RvE1-induced effects on phagocytosis compared with wild-type macrophages.

    “murine macrophages derived from ChemR23-deficient mice have increased production of pro-inflammatory cytokines105,117 and a lack of RvE1-induced effects on phagocytosis compared with wild-type macrophages105.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [105] Laguna-Fernandez, A. et al. ERV1/ChemR23 signaling protects from atherosclerosis by modifying oxLDL uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018). source

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    • cites [117] Lopez-Vicario, C. et al. Association of a variant in the gene encoding for ERV1/ChemR23 with reduced inflammation in visceral adipose tissue from morbidly obese individuals. Sci. Rep. 7, 15724 (2017). source

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    Interpretationreasoning

    Lesional macrophages are the principal target of Ac2-26 in these studies, although SPMs might also interact with lesional smooth muscle cells and endothelial cells.

    “Although the above data suggest that lesional macrophages are the principal target of Ac2–26 in these studies, SPMs might also interact with lesional smooth muscle cells and endothelial cells107,110.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [107] Ho, K. J. et al. Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis. Am. J. Pathol. 177, 2116–2123 (2010). source

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    • cites [110] Petri, M. H. et al. Aspirin-triggered 15-epi-lipoxin A4 signals through FPR2/ALX in vascular smooth muscle cells and protects against intimal hyperplasia after carotid ligation. Int. J. Cardiol. 179, 370–372 (2015). source

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    Premisecitation

    Specialized pro-resolving mediators inhibit the priming step and promote deactivation of the NLRP3 inflammasome in mouse macrophages.

    “the SPMs have been shown to inhibit the priming step and to promote the deactivation of the NLRP3 inflammasome in mouse macrophages67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Lopategi, A. et al. Frontline science: specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. J. Leukoc. Biol. 105, 25–36 (2018). source

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    Premisecitation

    ALX/FPR2 is the receptor for lipoxins, DHA-derived RvD1, and annexin A1, whereas EPA-derived resolvins signal through ChemR23.

    “ALX/FPR2 is the receptor for lipoxins, the DHA-derived RvD1 and for annexin A1 and its derivatives, whereas the EPA-derived resolvins signal their pro-resolving effects through the ChemR23 receptor103.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Bäck, M. et al. Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR review 7. Br. J. Pharmacol. 171, 3551–3574 (2014). source

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  • May combine two claims.

    Interpretationreasoning

    Extracellular and intracellular cholesterol accumulation incites NLRP3 inflammasome-dependent intimal inflammation, whereas HDL-mediated cholesterol removal quenches this inflammation.

    “Taken together, these findings show that extracellular and intracellular accumulation of cholesterol incites NLRP3 inflammasome-dependent intimal inflammation, whereas HDL-mediated cholesterol removal quenches the inflammation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Increased atherosclerosis burden in Apoe−/−Anxa1−/− mice compared with Apoe−/− mice can be reduced by the annexin A1 mimetic peptide Ac2-26, but this treatment does not affect lesion size in Apoe−/− mice lacking ALX/FPR2.

    “the increased atherosclerosis burden observed in Apoe−/−Anxa1−/− mice compared with Apoe−/− mice can be reduced by treatment with the annexin A1 mimetic peptide Ac2–26, whereas this treatment does not affect atherosclerotic lesion size in Apoe−/− mice lacking ALX/FPR2 (REF108).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Drechsler, M. et al. Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. Circ. Res. 116, 827–835 (2015). source

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    Premisecitation

    LXA4 administration with osmotic pumps to Apoe-knockout mice reduces atherosclerotic lesion size and inflammation, but does not alter the lesional phenotype of Apoe−/−Fpr2−/− mice.

    “LXA4 administration with osmotic pumps to Apoe-knockout mice reduces atherosclerotic lesion size and inflammation, whereas this treatment does not alter the lesional phenotype of Apoe−/−Fpr2−/− mice99.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Petri, M. H. et al. Aspirin-triggered lipoxin A4 inhibits atherosclerosis progression in apolipoprotein E−/− mice. Br. J. Pharmacol. 174, 4043–4054 (2017). source

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    Premisecitation

    Intraperitoneal injections of RvD1 to Western-diet-fed Ldlr-knockout mice with mid-stage atherosclerotic lesions restore RvD1 levels, increase efferocytosis, reduce oxidative stress, and induce a more stable plaque phenotype, suppressing progression to advanced lesions.

    “intraperitoneal injections of RvD1 to Western-diet-fed Ldlr-knockout mice with mid-stage atherosclerotic lesions restore RvD1 levels in the lesions, increase efferocytosis, reduce oxidative stress in the lesions and induce a more stable plaque phenotype, thereby suppressing the progression of the mid-stage lesions to more advanced lesions36.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Fredman, G. et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat. Commun. 7, 12859 (2016). source

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    Premisecitation

    OxLDL primes and activates the NLRP3 inflammasome in macrophages in mouse models of atherosclerosis: it primes via the CD36-TLR4-TLR6 complex and, after lysosomal transport, activates via cholesterol crystallization and lysosomal damage.

    “OxLDL has been shown both to prime and to activate the NLRP3 inflammasome in macrophages in mouse models of atherosclerosis: first, oxLDL primes the NLRP3 inflammasome by binding to the CD36–TLR4–TLR6 signalling complex on the macrophage surface and, then, after having been transported to lysosomes, the oxLDL activates the NLRP3 inflammasome via induction of cholesterol crystallization and ensuing”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [59] Sheedy, F. J. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14, 812–820 (2013). source

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    • cites [71] Duewell, P. & Latz, E. Assessment and quantification of crystal-induced lysosomal damage. Methods Mol. Biol. 1040, 19–27 (2013). source

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    Premisecitation

    Collagen-type-IV-targeted nanoparticles delivering Ac2-26 to established atherosclerotic lesions in Ldlr-knockout mice fed a Western diet increase lesional Ac2-26 levels and produce a more stable plaque phenotype compared with untargeted Ac2-26 nanoparticles.

    “Use of these nanoparticles to target the pro-resolving ALX/FPR2 agonist Ac2–26 to established atherosclerotic lesions in Ldlr-knockout mice fed a Western diet results in increased lesional Ac2–26 levels and a more stable plaque phenotype compared with mice receiving Ac2–26 nanoparticles without the collagen-type-IV-targeting peptide109.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Fredman, G. et al. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci. Transl Med. 7, 275ra220 (2015).

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    Premisecitation

    Oxidative, proteolytic, and lipolytic modifications induce LDL aggregation, and LDL aggregation susceptibility is associated with risk of cardiovascular death.

    “Oxidative, proteolytic and lipolytic modifications induce LDL aggregation46, and the aggregation susceptibility of LDL was shown to be associated with the risk of cardiovascular death55.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Öörni, K., Pentikäinen, M. O., Ala-Korpela, M. & Kovanen, P. T. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J. Lipid Res. 41, 1703–1714 (2000). source

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    • cites [55] Ruuth, M. et al. Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. Eur. Heart J. 39, 2562–2573 (2018). source

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  • May combine two claims.

    Interpretationreasoning

    Decreased levels of SPMs that signal through ALX/FPR2 suggest that pro-resolving signalling through this receptor might be perturbed in advanced atherosclerosis, consistent with a failure of inflammation resolution.

    “Given that both SPMs signal through ALX/ FPR2, their decreased levels in these patients suggest that the pro-resolving signalling through this receptor might be perturbed in advanced atherosclerosis, consistent with a failure in the resolution of inflammation.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Transcriptomic profiling of human atherosclerotic lesions revealed that CMKLR1 expression was positively associated with phagocytosis markers and negatively associated with VLDLR and SORT1 expression.

    “transcriptomic profiling of human atherosclerotic lesions revealing that the expression levels of CMKLR1, which encodes ChemR23, were positively associated with markers of phagocytosis (which is consistent with pro-resolving signalling) and negatively associated with VLDLR and SORT1 expression levels105.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Laguna-Fernandez, A. et al. ERV1/ChemR23 signaling protects from atherosclerosis by modifying oxLDL uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018). source

      Not checked in the free run.

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    Premisecitation

    Macrophages from ChemR23-deficient mice show a prolonged and continuous increase in oxLDL uptake in vitro, and atherosclerotic aortas of ChemR23-deficient mice show increased expression of genes related to lipid metabolism and lipoprotein uptake compared with wild-type.

    “macrophages from ChemR23-deficient mice show a prolonged and continuous increase in oxLDL uptake in vitro, and when compared with aortas of wild-type mice, the atherosclerotic aortas of the ChemR23-deficient mice showed increased expression of genes related to lipid metabolism and lipoprotein uptake105.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Laguna-Fernandez, A. et al. ERV1/ChemR23 signaling protects from atherosclerosis by modifying oxLDL uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018). source

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    Premisecitation

    Cholesterol can leave atherosclerotic plaque by three routes: efflux to HDL for blood return, emigration of foam cells carrying cholesterol, and efferocytosis of old foam cells by efflux-competent macrophages that may then leave the lesion.

    “Three mechanisms are available for cholesterol removal from the atherosclerotic plaque (FIG. 3).”
    • Also stated in: § Macrophage life cycle in atherosclerosis · plain
      “First, cholesterol can be effluxed from the macrophages to HDL particles for return transport to the blood137.”
    • Also stated in: § Macrophage life cycle in atherosclerosis · plain
      “The second mechanism is that the macrophage foam cells themselves leave the lesion and thus carry their cholesterol cargo back to the blood138.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [137] Talbot, C. P. J., Plat, J., Ritsch, A. & Mensink, R. P. Determinants of cholesterol efflux capacity in humans. Prog. Lipid Res. 69, 21–32 (2018). source

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    • cites [138] van Gils, J. M. et al. The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat. Immunol. 13, 136–143 (2012). source

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    Premisecitation

    The H2S donor sodium hydrosulfide reduces atherosclerosis in Apoe-knockout mice, whereas genetic targeting of the H2S synthesizing enzyme cystathionine γ-lyase exacerbates atherosclerosis in this model.

    “The H2S donor sodium hydrosulfide reduces atherosclerosis in Apoe -knockout mice132, whereas genetic targeting of the H2S synthesizing enzyme cystathionine γ-lyase exacerbates atherosclerosis in this model98.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [132] Wang, Y. et al. Role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 29, 173–179 (2009). source

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    • cites [98] Mani, S. et al. Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation 127, 2523–2534 (2013). source

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  • May combine two claims.

    Interpretationreasoning

    A decrease in H2S levels in atherosclerosis might lead to failure in resolution of atherosclerotic inflammation, raising the possibility that H2S donors could have a therapeutic role in cardiovascular disease prevention.

    “A decrease in H2S levels in atherosclerosis132 might, therefore, lead to a failure in the resolution of the atherosclerotic inflammation process, raising the possibility that H2S donors could have a therapeutic role in cardiovascular disease prevention.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Wang, Y. et al. Role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 29, 173–179 (2009). source

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    Premisecitation

    18-HEPE was identified as a major metabolite after EPA supplementation to hyperlipidaemic mice, suggesting that SPM levels can be restored by increasing substrate availability.

    “the RvE1 precursor 18-hydroxyeicosa-pentaenoic acid (18-HEPE) was identified as a major metabolite after EPA supplementation to hyperlipidae-mic mice105, suggesting that SPM levels can be restored by increasing substrate availability.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Laguna-Fernandez, A. et al. ERV1/ChemR23 signaling protects from atherosclerosis by modifying oxLDL uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018). source

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    Interpretationcitation

    ChemR23 localizes to a subset of lesional macrophages near the necrotic core, pointing to a specific role for RvE1-ChemR23 signalling in macrophages to limit necrotic core formation.

    “These findings, together with observations that ChemR23 localizes to a subset of lesional macrophages near the necrotic core105, point to a specific role for RvE1-ChemR23 signalling in macrophages to limit necrotic core formation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Laguna-Fernandez, A. et al. ERV1/ChemR23 signaling protects from atherosclerosis by modifying oxLDL uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018). source

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    Premisecitation

    H2S production in macrophages reduces LPS-induced TNF levels and stimulates efferocytosis of apoptotic granulocytes.

    “H2S production in macrophages reduces LPS-induced TNF levels and stimulates efferocytosis of apoptotic granulocytes131.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Dufton, N., Natividad, J., Verdu, E. F. & Wallace, J. L. Hydrogen sulfide and resolution of acute inflammation: a comparative study utilizing a novel fluorescent probe. Sci. Rep. 2, 499 (2012). source

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    Premisecitation

    ChemR23 deficiency in Apoe-knockout mice increases atherosclerotic lesion size and macrophage content.

    “ChemR23 deficiency in Apoe-knockout mice increases atherosclerotic lesion size and macrophage content105.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Laguna-Fernandez, A. et al. ERV1/ChemR23 signaling protects from atherosclerosis by modifying oxLDL uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018). source

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    Premisecitation

    Local macrophage proliferation and transdifferentiation of intimal smooth muscle cells into macrophage-like cells are further sources of lesional macrophages.

    “Local proliferation of macrophages and transdifferentiation of intimal smooth muscle cells into macrophage-like cells are two additional sources of macrophages in the lesions141.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Nagenborg, J., Goossens, P., Biessen, E. A. L. & Donners, M. Heterogeneity of atherosclerotic plaque macrophage origin, phenotype and functions: Implications for treatment. Eur. J. Pharmacol. 816, 14–24 (2017). source

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    Premisecitation

    Chemerin is a ChemR23 ligand present in human atherosclerotic lesions and correlates with disease severity.

    “The adipokine chemerin is another ChemR23 ligand116 that is present in human atherosclerotic lesions and correlates with disease severity106.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [116] Kennedy, A. J. & Davenport, A. P. International Union of Basic and Clinical Pharmacology CIII: chemerin receptors CMKLR1 (chemerin1) and GPR1 (chemerin2) nomenclature, pharmacology, and function. Pharmacol. Rev. 70, 174–196 (2018).

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    • cites [106] Kostopoulos, C. G., Spiroglou, S. G., Varakis, J. N., Apostolakis, E. & Papadaki, H. H. Chemerin and CMKLR1 expression in human arteries and periadventitial fat: a possible role for local chemerin in atherosclerosis? BMC Cardiovasc. Disord. 14, 56 (2014). source

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    Premisecitation

    CO may contribute to HO1's anti-inflammatory effects by restricting leukocyte entry into inflamed sites and reducing cytokine release.

    “CO might contribute to the anti-inflammatory functions of HO1 by limiting leukocyte infiltration into inflammatory sites and suppressing cytokine production130.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Wallace, J. L., Ianaro, A., Flannigan, K. L. & Cirino, G. Gaseous mediators in resolution of inflammation. Semin. Immunol. 27, 227–233 (2015). source

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  • May combine two claims.

    Premisecitation

    In murine zymosan-induced peritonitis, inhaled CO raises macrophage phagocytosis and lowers exudate granulocyte counts, thereby accelerating complete inflammation resolution.

    “In the murine zymosan-induced peritonitis model, inhaled CO increases macrophage phagocytosis and reduces granulocyte numbers in the exudate, thereby shortening the time to achieve complete resolution of inflammation133.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Chiang, N. et al. Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits. J. Immunol. 190, 6378–6388 (2013). source

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    Premisecitation

    Chimeric animals receiving ChemR23-deficient bone marrow transplantation show increased atherosclerotic lesion size, macrophage content, and necrotic core size.

    “Similar findings along with an increased necrotic core size were also observed in chimeric animals receiving ChemR23-deficient bone marrow transplantation105.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Laguna-Fernandez, A. et al. ERV1/ChemR23 signaling protects from atherosclerosis by modifying oxLDL uptake and phagocytosis in macrophages. Circulation 138, 1693–1705 (2018). source

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  • May combine two claims.

    Premisecitation

    Chemerin shows vasoconstrictor activity in vitro and increases blood pressure in mice.

    “Chemerin also shows vasoconstrictor activity in vitro and increases blood pressure in mice121.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Kunimoto, H. et al. Chemerin promotes the proliferation and migration of vascular smooth muscle and increases mouse blood pressure. Am. J. Physiol. Heart Circ. Physiol. 309, H1017–H1028 (2015). source

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    Premisecitation

    Chemerin is chemotactic for M1-like macrophages, exerts pro-inflammatory effects, and increases reactive oxygen species production in vascular cells.

    “Chemerin is a chemotactic molecule for M1-like macrophages114, exerts pro-inflammatory effects and increases the production of reactive oxygen species in vascular cells120.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [114] Herova, M., Schmid, M., Gemperle, C. & Hersberger, M. ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages. J. Immunol. 194, 2330–2337 (2015). source

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    • cites [120] Neves, K. B. et al. Chemerin regulates crosstalk between adipocytes and vascular cells through Nox. Hypertension 66, 657–666 (2015). source

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    Premisecitation

    ChemR23 deficiency in mice has different effects depending on the experimental model, for example reduced cerebral inflammation but exacerbated pulmonary inflammation.

    “ChemR23 deficiency in mice has different effects depending on the experimental model. For example, some models show reduced cerebral inflammation but exacerbated pulmonary inflammation116.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Kennedy, A. J. & Davenport, A. P. International Union of Basic and Clinical Pharmacology CIII: chemerin receptors CMKLR1 (chemerin1) and GPR1 (chemerin2) nomenclature, pharmacology, and function. Pharmacol. Rev. 70, 174–196 (2018).

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    Premisecitation

    In adult mice at steady state, nonclassical Ly6Clow monocytes patrol microcirculation vessels and are important for endothelial homeostasis and inflammation.

    “In adult mice under physiological, steady-state conditions, the circulating, nonclassical Ly6Clow monocytes remain in the circulation and patrol the vessels of the microcirculation, where these monocytes are critical for endothelial homeostasis and inflammation145.”
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    • cites [145] Ensan, S. et al. Self-renewing resident arterial macrophages arise from embryonic CX3CR1+ precursors and circulating monocytes immediately after birth. Nat. Immunol. 17, 159–168 (2016). source

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    Premisecitation

    Nonclassical monocytes also patrol large-artery endothelium, and this patrolling is strongly increased in hyperlipidaemia and atherosclerosis, improving endothelial protection in the inflamed, high-shear, pulsatile environment of developing lesions.

    “However, a 2017 study in mice revealed that these nonclassical monocytes also patrol the endothelium of large arteries, and this type of arterial patrolling is highly upregulated in hyperlipidaemia and atherosclerosis, thereby allowing improved protection of the arterial endothelium in the inflamed, high-shear stress and pulsatile environment of a developing atherosclerotic lesion146.”
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    • cites [146] Quintar, A. et al. Endothelial protective monocyte patrolling in large arteries intensified by western diet and atherosclerosis. Circ. Res. 120, 1789–1799 (2017). source

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    Premisecitation

    Necroptosis contributes to atherosclerosis and is active in unstable human atherosclerotic lesions.

    “Necroptosis has been shown to have a role in atherosclerosis and, importantly, this form of cell death has been shown to be active in unstable atherosclerotic lesions in humans169.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [169] Karunakaran, D. et al. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Sci. Adv. 2, e1600224 (2016). source

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    Premisecitation

    Single-cell analyses of unique macrophage subsets such as TREM2+ macrophages have revealed extensive phenotypic heterogeneity of macrophages and monocyte-derived dendritic cells in atherosclerotic lesions and produced a novel immune cell atlas of atherosclerosis.

    “Indeed, findings on unique macrophage subsets (such as TREM2+ macrophages) on the basis of single-cell analyses have uncovered unprecedented phenotypic heterogeneity of macrophages and monocyte-derived dendritic cells in atherosclerotic lesions and have defined a novel atlas of the immune cell repertoire in atherosclerosis135,154.”
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    • cites [135] Winkels, H. et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ. Res. 122, 1675–1688 (2018). source

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    • cites [154] Cochain, C. et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122, 1661–1674 (2018). source

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    Premisecitation

    In humans, intimal macrophages derive from classical CD14+CD16- monocytes, which are the predominant blood monocytes and are preferentially recruited to inflammatory sites including atherosclerotic plaques.

    “In humans, the macrophages in the arterial intima derive from the classical CD14+CD16- monocytes, which predominate in the circulating blood and are preferentially recruited into inflammatory sites, including the atherosclerotic plaques148.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Gautier, E. L., Jakubzick, C. & Randolph, G. J. Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 1412–1418 (2009). source

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    Premisecitation

    These tissue-resident macrophages self-renew and perform homeostatic and physiological tissue functions.

    “These macrophages self-renew and fulfil homeostatic and physiological functions in the tissue concerned144.”
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    • cites [144] Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013). source

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    Premisecitation

    SPM biosynthesis is greater in M2-like macrophages than in M1-like macrophages and rises further after efferocytosis.

    “In addition, SPM biosynthesis is higher in M2-like macrophages than in M1-like macrophages and increases further in response to efferocytosis161.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Dalli, J. & Serhan, C. Macrophage proresolving mediators — the when and where. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.MCHD-0001-2014 (2016). source

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    Premisecitation

    In Apoe-/- mice, a necrostatin 1-based radiotracer localized specifically to atherosclerotic plaques, and necrostatin 1 treatment reduced lesion size and markers of plaque instability such as necrotic core formation.

    “In this study, a radiotracer developed with the small-molecule inhibitor of necroptosis, necrostatin 1, localized specifically to atherosclerotic plaques in Apoe- /- mice, and treatment of Apoe- /- mice with necro-statin 1 reduced atherosclerotic lesion size and markers of plaque instability, such as necrotic core formation169.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [169] Karunakaran, D. et al. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Sci. Adv. 2, e1600224 (2016). source

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    Premisecitation

    GM-CSF and M-CSF are widely expressed in the vascular wall and regulate monocyte-to-macrophage differentiation as well as mature macrophage number and function.

    “Two colony-stimulating factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), are widely expressed in the vascular wall149.”
    • Also stated in: § Macrophage origin and subsets · plain
      “These factors regulate not only monocyte-to-macrophage differentiation but also the number and function of mature macrophages150.”
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    • cites [149] Di Gregoli, K. & Johnson, J. L. Role of colony-stimulating factors in atherosclerosis. Curr. Opin. Lipidol. 23, 412–421 (2012). source

      Not checked in the free run.

    • cites [150] Ushach, I. & Zlotnik, A. Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage. J. Leukoc. Biol. 100, 481–489 (2016). source

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    Premisecitation

    SPMs improve cell survival and reduce NLRP3 inflammasome activation in macrophages.

    “Conversely, SPMs improve cell survival171,172 and decrease NLRP3 inflammasome activation in macro-phages67.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [171] Mai, J. et al. The atheroprotective role of lipoxin A4 prevents oxLDL-induced apoptotic signaling in macrophages via JNK pathway. Atherosclerosis 278, 259–268 (2018). source

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    • cites [172] Prieto, P. et al. Activation of autophagy in macrophages by pro-resolving lipid mediators. Autophagy 11, 1729–1744 (2015). source

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    • cites [67] Lopategi, A. et al. Frontline science: specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. J. Leukoc. Biol. 105, 25–36 (2018). source

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    Premisecitation

    Continuous Ly6Chigh monocyte influx and differentiation into macrophages without egress causes total macrophage mass to grow, with older macrophages deep and younger ones superficial in the lesion.

    “Second, continuous influx of Ly6Chigh monocytes and their differentiation into macrophages in the absence of macrophage egress from the atherosclerotic lesion leads to an ongoing increase in the total mass of macrophages, with the oldest macrophages in the deep layers and the youngest ones in the superficial layers of the lesion140.”
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    • cites [140] Williams, J. W. et al. Limited macrophage positional dynamics in progressing or regressing murine atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol. 38, 1702–1710 (2018). source

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    Premisecitation

    In cultured macrophages, modified lipoproteins such as oxLDL induce autophagy, apoptosis, pyroptosis through NLRP3 inflammasome activation, and necroptosis.

    “Uptake of modified lipoproteins, such as oxLDL, has been shown in cultured macrophages to induce autophagy168, apoptosis170, pyroptosis (via induction of NRLP3 inflammasome activation72) and necroptosis169.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [168] Ouimet, M. et al. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 13, 655–667 (2011). source

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    • cites [170] Andres, V., Pello, O. M. & Silvestre-Roig, C. Macrophage proliferation and apoptosis in atherosclerosis. Curr. Opin. Lipidol. 23, 429–438 (2012). source

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    • cites [72] Grebe, A., Hoss, F. & Latz, E. NLRP3 inflammasome and the IL-1 pathway in atherosclerosis. Circ. Res. 122, 1722–1740 (2018). source

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    Premisecitation

    SPMs and IL-10 promote efferocytosis.

    “Both SPMs and IL-10 promote efferocytosis36,93,181–185”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [36] Fredman, G. et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat. Commun. 7, 12859 (2016). source

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    • cites [93] Kasikara, C., Doran, A. C., Cai, B. & Tabas, I. The role of non-resolving inflammation in atherosclerosis. J. Clin. Invest. 128, 2713–2723 (2018). source

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    • cites [181] Krishnamoorthy, S., Recchiuti, A., Chiang, N., Fredman, G. & Serhan, C. N. Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. Am. J. Pathol. 180, 2018–2027 (2012). source

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    • cites [182] Godson, C. et al. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J. Immunol. 164, 1663–1667 (2000). source

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    • cites [183] Mitchell, S. et al. Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo. J. Am. Soc. Nephrol. 13, 2497–2507 (2002). source

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    • cites [184] Campana, L. et al. The STAT3-IL-10-IL-6 pathway is a novel regulator of macrophage efferocytosis and phenotypic conversion in sterile liver injury. J. Immunol. 200, 1169–1187 (2018). source

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    • cites [185] Ogden, C. A. et al. Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt’s lymphoma. J. Immunol. 174, 3015–3023 (2005). source

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    Premisecitation

    Lipid-lowering interventions in atherosclerotic mice appear to attenuate arterial-wall lipoprotein modification and promote a pro-resolving phenotype in lesional macrophages, both preceding plaque regression.

    “Indeed, lipid-lowering interventions in atherosclerotic mice seem both to attenuate lipoprotein modification in the arterial wall and to promote a pro-resolving phenotype in lesional macrophages, all of which precede plaque regression209.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [209] Feig, J. E. et al. Regression of atherosclerosis is characterized by broad changes in the plaque macrophage transcriptome. PLOS ONE 7, e39790 (2012). source

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    Premisecitation

    Although monocyte-derived macrophages are the predominant phagocytic cells in developing atherosclerotic plaques, their efferocytosis capacity becomes impaired during atherosclerosis progression.

    “Although the predominant cell type in developing atherosclerotic plaques is phagocytic monocyte-derived macrophages, the capacity of these cells to execute efferocytosis is impaired during atherosclerosis progression177.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Yurdagul, A. et al. Mechanisms and consequences of defective efferocytosis in atherosclerosis. Front. Cardiovasc. Med. 4, 86 (2017). source

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    Premisecitation

    Blocking antibodies against TIM1 or TIM4 promote atherosclerosis progression in mice by preventing lesional efferocytosis, causing accumulation of secondarily necrotic cells and synthesis of pro-inflammatory cytokines.

    “Treatment with blocking antibodies against TIM1 or TIM4 promotes the progression of atherosclerosis in mice by preventing efferocytosis in the atherosclerotic lesion, leading to the accumulation of secondarily necrotic cells and the synthesis of pro-inflammatory cytokines201.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [201] Foks, A. C. et al. Blockade of Tim-1 and Tim-4 enhances atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 36, 456–465 (2016). source

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    Premisecitation

    Mice lacking MERTK or expressing a constitutively inactive MERTK have larger plaques and greater necrotic core area than control mice.

    “Conversely, mice lacking MERTK or expressing a constitutively inactive form of MERTK show larger plaque size and increased necrotic core area compared with control mice196,197.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [196] Thorp, E., Cui, D., Schrijvers, D. M., Kuriakose, G. & Tabas, I. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe−/− mice. Arterioscler. Thromb. Vasc. Biol. 28, 1421–1428 (2008). source

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    • cites [197] Ait-Oufella, H. et al. Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28, 1429–1431 (2008). source

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  • May combine two claims.

    Premisecitation

    Anti-IL-1β antibody therapy was associated with a small but significant increase in certain fatal infections, explainable by the host defence-compromising potential of pure anti-inflammatory therapy.

    “Unfortunately, the anti-IL-1β antibody therapy was associated with a small but significant increase in certain fatal infections212, which can be explained by the host defence-compromising potential of a pure anti-inflammatory therapy33.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [212] Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017). source

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    • cites [33] Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013). source

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    Interpretationcitation

    This resolution concept is likely relevant to humans because large reductions in plasma LDL-cholesterol cause regression of even advanced atherosclerotic lesions, and plaque regression is accompanied by fewer atherosclerotic cardiovascular disease events.

    “This concept is likely to be relevant to humans because dramatic reductions in plasma LDL-cholesterol levels lead to the regression of even advanced atherosclerotic lesions, and plaque regression is accompanied by lower rates of atherosclerotic cardiovascular disease events210,211.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [210] Tang, X. et al. The effect of statin therapy on plaque regression following acute coronary syndrome: a meta-analysis of prospective trials. Coron. Artery Dis. 27, 636–649 (2016). source

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    • cites [211] Rosenson, R. S., Hegele, R. A., Fazio, S. & Cannon, C. P. The evolving future of PCSK9 inhibitors. J. Am. Coll. Cardiol. 72, 314–329 (2018). source

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    Premisecitation

    SPMs suppress inflammation but, unlike anti-inflammatory drugs, promote both repair and continued pathogen clearance.

    “From a translational perspective, SPMs suppress inflammation but, unlike anti-inflammatory drugs, these pro-resolving mediators promote both repair and continued pathogen clearance33,213–215.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [33] Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013). source

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    • cites [213] Dalli, J. & Serhan, C. N. Identification and structure elucidation of the pro-resolving mediators provides novel leads for resolution pharmacology. Br. J. Pharmacol. https://doi.org/10.1111/bph.14336 (2018). source

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    • cites [214] Chiang, N. et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524–528 (2012). source

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    • cites [215] Spite, M. et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461, 1287–1291 (2009). source

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    Premisecitation

    Apoe−/− mice with Cdkn2b deletion had lower calreticulin than control Apoe−/− mice, and Cdkn2b−/−Apoe−/− mice on a Western diet had larger plaques and necrotic cores than controls, attributed to intralesional apoptotic cells resisting phagocytosis.

    “For example, Apoe−/− mice with deletion of Cdkn2b had lower levels of calreticulin than control Apoe−/− mice, and Cdkn2b−/−Apoe−/− mice fed a Western diet had increased plaque size and larger necrotic core area than control Apoe−/− mice, which was attributed to intralesional apoptotic cells being resistant to phagocytosis203.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Kojima, Y. et al. Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis. J. Clin. Invest. 124, 1083–1097 (2014). source

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  • May combine two claims.

    Interpretationreasoning

    As atherogenesis advances, the inflammatory response fails to resolve properly and thereby further sustains leukocyte recruitment.

    “With advancing atherogenesis, this inflammatory response fails to resolve properly, which further sustains leukocyte recruitment.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    These atheromas are especially sensitive to necrotic cell accumulation and to loss of the anti-inflammatory and pro-resolving responses inherent to efferocytosis.

    “These atheromas are particularly sensitive to the accumulation of necrotic cells and to the loss of anti-inflammatory and pro-resolving responses that, as mentioned above, are inherent to the efferocytosis programme.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Deletion of Scarb1 in macrophages causes defective efferocytosis in vitro and increased plaque size, necrotic core area and inflammation in vivo.

    “In addition, deletion of Scarb1 (encoding SRB1) in macrophages results in defective efferocytosis in vitro and increased plaque size, necrotic core area and inflammation in vivo202.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Tao, H. et al. Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. J. Lipid Res. 56, 1449–1460 (2015). source

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  • May combine two claims.

    Premisecitation

    Soluble MER rises in advancing atherosclerosis in mice and humans and can compete with MERTK for GAS6 and protein S binding, thereby compromising lesional efferocytosis.

    “Levels of the cleaved product, soluble MER, increase in advancing atherosclerosis in both mice and humans and can compete with MERTK for binding of GAS6 and protein S and thereby compromise efferocytosis in the lesion162.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Cai, B. et al. MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J. Clin. Invest. 127, 564–568 (2017). source

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  • May combine two claims.

    Premisecitation

    CD47-blocking antibodies given to Apoe−/− mice on a high-fat diet increase lesional efferocytosis and reduce necrotic core formation.

    “Accordingly, delivery of CD47-blocking antibodies to Apoe−/− mice fed a high-fat diet increases efferocytosis in the atherosclerotic lesion and reduces necrotic core formation207.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [207] Kojima, Y. et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536, 86–90 (2016). source

      Not checked in the free run.

68 of 68

  • The paper relies on this without support.

    Findings from mouse models of atherosclerosis are relevant to human atherosclerotic disease and to the therapeutic potential of pro-resolving mediators.

    “These model systems are relevant to NLRP3 inflammasome activation in human atherosclerosis because necrotic cells release various DAMPs, among them ATP, and the concentration of circulating albumin-bound palmitate is elevated in states of insulin resistance and type 2 diabetes mellitus69,70.”

  • The paper relies on this without support.

    The ratio of specialized pro-resolving mediators to leukotrienes in atherosclerotic lesions reflects the functional balance between pro-resolving and pro-inflammatory signalling.

    “In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions.”

  • The paper relies on this without support.

    Resolution of local inflammation and regression of atherosclerotic lesions strongly depend on macrophages.

    “The resolution of local inflammation and, most importantly, the regression of an atherosclerotic lesion strongly depend on macrophages; therefore, a better understanding of the physiological and pathophysiological control of the checkpoints of the macrophage life cycle in atherosclerotic lesions is vital.”

  • The paper relies on this without support.

    Infiltration and accumulation of atherogenic plasma lipoproteins is the driving force of atherogenesis.

    “Because infiltration and accumulation of the atherogenic plasma lipoproteins is the driving force of atherogenesis, removal of these lipoproteins in the developing lesions through their uptake and degradation is the primary function of the intimal macrophages.”

  • The paper relies on this without support.

    The necrotic core is the primary feature of atherosclerotic plaque vulnerability, causing susceptibility to rupture and lumenal thrombosis, the primary causes of clinical complications.

    “The necrotic core is the primary feature of atherosclerotic plaque vulnerability, which renders lesions susceptible to rupture and lumenal thrombosis, the primary causes of clinical complications of atherosclerotic cardiovascular diseases.”

  • The paper relies on this without support.

    Lipid accumulation in the arterial intima is the root cause of inflammatory atherosclerotic lesion formation.

    “In atherogenesis, lipid accumulation in the arterial intima is the root cause of the formation of inflammatory atherosclerotic lesions.”
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?

  • Since the plaque milieu suppresses efferocytosis, uncleared apoptotic cells undergo secondary necrosis with release of DAMPs.

    “Since the plaque milieu suppresses efferocytosis 133-136 , uncleared apoptotic cells subsequently undergo secondary necrosis with release of further inflammatory material, such as damage-associated molecular patterns (DAMPs) 137 .”

    From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [137]

  • Defective efferocytosis of apoptotic cells leading to secondary necrosis and leakage of intracellular contents has been proposed to exacerbate the inflammatory milieu.

    “defective efferocytosis of apoptotic cells leading to secondary necrosis and leakage of intracellular contents has been proposed to exacerbate the inflammatory milieu 131,132,137 .”

    From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [137]

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Authors
Bäck, M., Yurdagul, A., Tabas, I., Öörni, K., & Kovanen, P. T.
Affiliations
  • Karolinska University Hospital (SE)
  • Columbia University Irving Medical Center (US)
  • University of Helsinki (FI)
  • Wihuri Research Institute (FI)
Corresponding author
Kovanen, Petri T.
ORCID
Venue
Nature Reviews Cardiology
Publisher
Springer Science and Business Media LLC
Published
2019-03-07
Volume
16
Issue
7
Pages
389-406
ISSN
  • 1759-5002 (ISSN-L)
  • 1759-5010
DOI
10.1038/s41569-019-0169-2
PMC
PMC6727648
OpenAlex
W2920248606
Cited by
1,341
References
219
Citations by year
2026: 69 · 2025: 174 · 2024: 223 · 2023: 234 · 2022: 257 · 2021: 213 · 2020: 127 · 2019: 40
FWCI
13.74
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (K99HL145131, R01HL132412, R01HL140554, R01HL127464, P01HL087123, R01HL075662, R01HL107497, R35HL145228, T32HL007343)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
atherosclerosis, inflammation resolution, specialized pro-resolving mediators, omega-3 fatty acids, arachidonic acid, efferocytosis, foam cells, macrophages, plaque vulnerability, leukotrienes, pro-inflammatory lipids, atherosclerotic plaque formation, anti-inflammatory therapy
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Humans, Inflammation, Lipoproteins, Macrophages, Signal Transduction, Apoptosis, Tunica Intima, Atherosclerosis, Lipid Metabolism, Inflammasomes

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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 2026-10-06.

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