ATP release and purinergic signaling: a common pathway for particle-mediated inflammasome activation.
Deposition of uric acid crystals in joints causes the acute and chronic inflammatory disease known as gout and prolonged airway exposure to silica crystals leads to the development of silicosis, an irreversible fibrotic pulmonary disease. Aluminum salt (Alum) crystals are frequently used as vaccine adjuvant. The mechanisms by which crystals activate innate immunity through the Nlrp3 inflammasome are not well understood. Here, we show that uric acid, silica and Alum crystals trigger the extracellular delivery of endogenous ATP, which just precedes the secretion of mature interleukin-1β (IL-1β) by macrophages, both events depending on purinergic receptors and connexin/pannexin channels. Interestingly, not only ATP but also ADP and UTP are involved in IL-1β production upon these Nlrp3 inflammasome activators through multiple purinergic receptor signaling. These findings support a pivotal role for nucleotides as danger signals and provide a new molecular mechanism to explain how chemically and structurally diverse stimuli can activate the Nlrp3 inflammasome.
University of Orleans, CNRS, UMR7355, INEM, Transgenose Institute, Orleans, France.
N
N
Riteau
L
L
Baron
B
B
Villeret
N
N
Guillou
F
F
Savigny
B
B
Ryffel
F
F
Rassendren
M
M
Le Bert
A
A
Gombault
I
I
Couillin
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000535:Aluminum / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D017630:Connexins / Q000378:metabolism; D057056:Cysteine Proteases / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011983:Receptors, Purinergic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000737:chemistry / Q000494:pharmacology; D014527:Uric Acid / Q000737:chemistry / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000378:metabolism
D002352:Carrier Proteins; D017630:Connexins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011983:Receptors, Purinergic; D014527:Uric Acid; D000244:Adenosine Diphosphate; D012822:Silicon Dioxide; D000255:Adenosine Triphosphate; D000535:Aluminum; D057056:Cysteine Proteases; D014544:Uridine Triphosphate