CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation
Frederick J. Sheedy,Alena Grebe,Katey J. Rayner,Parisa Kalantari,Bhama Ramkhelawon,Susan Carpenter,Christine Becker,Hasini Ediriweera,Adam E. Mullick,Douglas T. Golenbock,Lynda M. Stuart,Eicke Latz,Eicke Latz,Eicke Latz,Katherine A. Fitzgerald,Kathryn J. Moore +15 more
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TLDR
This work identifies an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome in sterile inflammation.Abstract:
Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1β (IL-1β) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-β and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1β production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1β and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.read more
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Rapamycin regulates macrophage activation by inhibiting NLRP3 inflammasome-p38 MAPK-NFκB pathways in autophagy- and p62-dependent manners
TL;DR: It is demonstrated that autophagy induction by rapamycin suppressed the production of IL-1β and IL-18 in lipopolysaccharide- and adenosine triphosphate-activated macrophages at the post-transcriptional level by eliminating mitochondrial ROS and pro-IL1β in a p62/SQSTM1-dependent manner.
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Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice.
Benoit Pourcet,Mathilde Zecchin,Lise Ferri,Justine Beauchamp,Sadicha Sitaula,Cyrielle Billon,Stéphane Delhaye,Jonathan Vanhoutte,Alicia Mayeuf-Louchart,Quentin Thorel,Joel T. Haas,Jérôme Eeckhoute,David Dombrowicz,Christian Duhem,Alexis Boulinguiez,Steve Lancel,Yasmine Sebti,Thomas P. Burris,Bart Staels,Hélène Duez +19 more
TL;DR: In studies of Nr1d1-/- mice and human macrophages with pharmacologic activation of NR1D1, it is found NR 1D1 to regulate the timing of NLRP3 expression and production of inflammatory cytokines by macrophage.
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CD36 in chronic kidney disease: novel insights and therapeutic opportunities
Xiaochun Yang,Daryl M. Okamura,Xifeng Lu,Yaxi Chen,John F. Moorhead,Zac Varghese,Xiong Z. Ruan,Xiong Z. Ruan +7 more
TL;DR: The regulation and post-translational modification of CD36, its role in renal pathophysiology and its potential as a biomarker and as a therapeutic target for the prevention of kidney fibrosis are discussed.
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Macrophage Recognition of Crystals and Nanoparticles
TL;DR: This review focuses on the mechanisms by which macrophages recognize crystals and nanoparticles and a model for receptor-independent phagocytosis of crystals has been proposed.
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Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer's disease models: effects of aging and amyloid pathology
TL;DR: The data indicate that microglia and MDM display distinct phenotypes in AD models and highlight the specific effects of normal aging vs Aβ peptides on inflammatory processes that occur during the disease progression.
References
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A role for mitochondria in NLRP3 inflammasome activation
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NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Peter Duewell,Hajime Kono,Katey J. Rayner,Katey J. Rayner,Cherilyn M. Sirois,Gregory I. Vladimer,Franz Bauernfeind,George S. Abela,Luigi Franchi,Guillermo Gabriel Nuñez,Max Schnurr,Terje Espevik,Egil Lien,Katherine A. Fitzgerald,Kenneth L. Rock,Kathryn J. Moore,Kathryn J. Moore,Samuel D. Wright,Veit Hornung,Eicke Latz,Eicke Latz +20 more
TL;DR: It is shown that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage and that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation.
Journal ArticleDOI
Cryopyrin activates the inflammasome in response to toxins and ATP
Sanjeev Mariathasan,David S. Weiss,Kim Newton,Jacqueline McBride,Karen O'Rourke,Meron Roose-Girma,Wyne P. Lee,Yvette Weinrauch,Denise M. Monack,Vishva M. Dixit +9 more
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Journal ArticleDOI
Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization
Veit Hornung,Franz Bauernfeind,Annett Halle,Eivind O. Samstad,Eivind O. Samstad,Hajime Kono,Kenneth L. Rock,Katherine A. Fitzgerald,Eicke Latz,Eicke Latz +9 more
TL;DR: It is demonstrated that silica and aluminum salt crystals activated inflammasomes formed by the cytoplasmic receptor NALP3, which senses lysosomal damage as an endogenous 'danger' signal.
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Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
Franz Bauernfeind,Gabor Horvath,Andrea Stutz,Emad S. Alnemri,Kelly S. MacDonald,David P. Speert,Teresa Fernandes-Alnemri,Jianghong Wu,Brian G. Monks,Katherine A. Fitzgerald,Veit Hornung,Eicke Latz +11 more
TL;DR: It is shown that cell priming through multiple signaling receptors induces NLRP3 expression, which is identified to be a critical checkpoint for NLRP2 activation and signals provided by NF-κB activators are necessary but not sufficient forNLRP3 activation.
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