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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The inflammasome in myocardial injury and cardiac remodeling.
Stefano Toldo,Eleonora Mezzaroma,Adolfo G Mauro,Fadi N Salloum,Benjamin W. Van Tassell,Antonio Abbate +5 more
TL;DR: The activation of the inflammasome in the heart during ischemic and nonischemic injury represents an exaggerated response to sterile injury and promotes adverse cardiac remodeling and failure.
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Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics
Andisheh Abedini,Annette Plesner,Ping Cao,Zachary Ridgway,Jinghua Zhang,Ling Hsien Tu,Chris T. Middleton,Brian Chao,Daniel J. Sartori,Fanling Meng,Hui Wang,Amy G. Wong,Martin T. Zanni,C. Bruce Verchere,Daniel P. Raleigh,Ann Marie Schmidt +15 more
TL;DR: The toxic species produced during IAPP amyloid formation are defined and their properties linked to induction of rat INS-1 β-cell and murine islet toxicity are linked, highlighting the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidsogenic polypeptides.
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Genomics of Alzheimer Disease: A Review
TL;DR: A comprehensive review of knowledge of the genomics of Alzheimer disease and DNA amyloid β 42 (Aβ42) vaccination as a potential therapy is provided in this article. But it is difficult to obtain a detailed analysis of all the genes associated with AD.
Journal ArticleDOI
NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages.
Yan-Gang Liu,Ji-Kuai Chen,Zi-Teng Zhang,Xiu-Juan Ma,Yong-Chun Chen,Xiu-Ming Du,Hong Liu,Ying Zong,Guo-Cai Lu +8 more
TL;DR: The role of NLRP3 inflammasome activation and the secondary pyroptosis underlying radiation-induced immune cell death in BMDMs is explored and it is concluded that the NLRP2 inflammaome activation mediates radiation- induced pyroPTosis in B MDMs.
Journal ArticleDOI
CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis
Lei Zhao,Chang Zhang,Xiaoxiao Luo,Pei Wang,Wei Zhou,Shan Zhong,Yunxia Xie,Yibo Jiang,Ping Yang,Renkuang Tang,Qin Pan,Andrew Hall,Tu Vinh Luong,Jian-Gao Fan,Zac Varghese,John F. Moorhead,Massimo Pinzani,Yaxi Chen,Xiong Z. Ruan,Xiong Z. Ruan,Xiong Z. Ruan +20 more
TL;DR: The present study demonstrated that the localization of CD36 on the plasma membrane of hepatocytes is increased in patients with non-alcoholic steatohepatitis and demonstrated the key role of palmitoylation in regulating CD36 distributions and its functions in NASH.
References
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NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
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Cryopyrin activates the inflammasome in response to toxins and ATP
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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
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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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