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| Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase-1 |
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| Author(s): Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Berlin J, Coyle AJ, Galan JE, Askenase PW, Flavell RA |
| Source: IMMUNITY Volume: 24 Issue: 3 Pages: 317-327 Published: MAR 2006 |
| Times Cited: 200 References: 40 |
| Abstract: 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-IL1 beta-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-1 alpha, IL-1 beta, and IL-18. IL-1 beta 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Flavell, RA (reprint author), Yale Univ, Sch Med, Immunobiol Sect, 333 Cedar St, New Haven, CT 06520 USA |
Addresses:
1. Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA
2. Yale Univ, Sch Med, Infect Dis Sect, New Haven, CT 06520 USA
3. Yale Univ, Sch Med, Allergy & Clin Immunol Sect, New Haven, CT 06520 USA
4. Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA
5. Jagiellonian Univ, Sch Med, Dept Human Dev Biol, Krakow, Poland
6. Yale Univ, Sch Med, Boyer Ctr Mol Med, Sect Microbial Pathogenesis, New Haven, CT 06536 USA
7. Millennium Pharmaceut Inc, Cambridge, MA 02139 USA |
| Publisher: CELL PRESS, 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA |
| Subject Category: Immunology |
| IDS Number: 028QY |
| ISSN: 1074-7613 |
| DOI: 10.1016/j.immuni.2006.02.004 |
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