Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1.
Mutations in the NALP3/CIAS1/cryopyrin gene are linked to three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous and articular syndrome. NALP3, with the adaptor molecule ASC, has been proposed to form a caspase-1-activating "inflammasome," a complex with pro-IL1beta-processing activity. Here, we demonstrate the effect of NALP3 deficiency on caspase-1 function. NALP3 was essential for the ATP-driven activation of caspase-1 in lipopolysaccharide-stimulated macrophages and for the efficient secretion of the caspase-1-dependent cytokines IL-1alpha, IL-1beta, and IL-18. IL-1beta has been shown to play a key role in contact hypersensitivity; we show that ASC- and NALP3-deficient mice also demonstrate an impaired contact hypersensitivity response to the hapten trinitrophenylchloride. NALP3, however, was not required for caspase-1 activation by Salmonella typhimurium, and NALP3 deficiency only partially protects mice from the lethal effects of endotoxin. These data suggest that NALP3 plays a specific role in the caspase-1 activation pathway.
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Fayyaz S
FS
Sutterwala
Yasunori
Y
Ogura
Marian
M
Szczepanik
Maria
M
Lara-Tejero
G Scott
GS
Lichtenberger
Ethan P
EP
Grant
John
J
Bertin
Anthony J
AJ
Coyle
Jorge E
JE
Galán
Philip W
PW
Askenase
Richard A
RA
Flavell
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001327:Autoimmune Diseases / Q000209:etiology; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000502:physiology; D004789:Enzyme Activation; D007113:Immunity, Innate; D007375:Interleukin-1 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger / Q000032:analysis; D012486:Salmonella typhimurium / Q000276:immunology; D012772:Shock, Septic / Q000209:etiology; D051193:Toll-Like Receptors / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D000255:Adenosine Triphosphate; D020170:Caspase 1