Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells.
BACKGROUND
Pleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear.


RESULTS
We document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1β, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model.


CONCLUSIONS
These novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis.
Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA.
Jedd M
JM
Hillegass
Jill M
JM
Miller
Maximilian B
MB
MacPherson
Catherine M
CM
Westbom
Mutlay
M
Sayan
Joyce K
JK
Thompson
Sherrill L
SL
Macura
Timothy N
TN
Perkins
Stacie L
SL
Beuschel
Vlada
V
Alexeeva
Harvey I
HI
Pass
Chad
C
Steele
Brooke T
BT
Mossman
Arti
A
Shukla
D000818:Animals; D017638:Asbestos, Crocidolite / Q000633:toxicity*; D019898:Autocrine Communication; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D008654:Mesothelioma / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D017641:Zeolites / Q000633:toxicity*
D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D017638:Asbestos, Crocidolite; C083174:erionite; D017641:Zeolites