title: Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice.
abstract: Missense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), the most common Mendelian autoinflammatory disease. However, it remains controversial as to whether FMF is due to the loss of an inhibitor of inflammation or to the activity of a proinflammatory molecule. We generated both pyrin-deficient mice and "knockin" mice harboring mutant human B30.2 domains. Homozygous knockin, but not pyrin-deficient, mice exhibited spontaneous bone marrow-dependent inflammation similar to but more severe than human FMF. Caspase-1 was constitutively activated in knockin macrophages and active IL-1β was secreted when stimulated with lipopolysaccharide alone, which is also observed in FMF patients. The inflammatory phenotype of knockin mice was completely ablated by crossing with IL-1 receptor-deficient or adaptor molecule ASC-deficient mice, but not NLRP3-deficient mice. Thus, our data provide evidence for an ASC-dependent NLRP3-independent inflammasome in which gain-of-function pyrin mutations cause autoinflammatory disease.
authors: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. chaej@mail.nih.gov
authors: Jae Jin
authors: JJ
authors: Chae
authors: Young-Hun
authors: YH
authors: Cho
authors: Geun-Shik
authors: GS
authors: Lee
authors: Jun
authors: J
authors: Cheng
authors: P Paul
authors: PP
authors: Liu
authors: Lionel
authors: L
authors: Feigenbaum
authors: Stephen I
authors: SI
authors: Katz
authors: Daniel L
authors: DL
authors: Kastner
references: Blood. 2000 May 15;95(10):3223-31
references: 10807793
references: Ann Intern Med. 2007 Jun 5;146(11):825-6
references: 17548423
references: Immunity. 2009 Jun 19;30(6):875-87
references: 19501000
references: Arthritis Rheum. 2009 Jun;60(6):1851-61
references: 19479870
references: Arthritis Rheum. 2009 Jun;60(6):1575-7
references: 19479854
references: Annu Rev Immunol. 2009;27:621-68
references: 19302049
references: Hum Mutat. 2004 Sep;24(3):194-8
references: 15300846
references: Cell Death Differ. 2007 Aug;14(8):1457-66
references: 17431422
references: Nat Genet. 2001 Mar;27(3):318-21
references: 11242116
references: Ann Rheum Dis. 2007 Nov;66(11):1545-6
references: 17934085
references: Mol Cell. 2007 Oct 26;28(2):214-27
references: 17964261
references: Curr Opin Immunol. 2000 Aug;12(4):479-86
references: 10899034
references: Blood. 2008 Sep 1;112(5):1794-803
references: 18577712
references: Rheumatology (Oxford). 2006 Jun;45(6):746-50
references: 16403826
references: Br J Haematol. 2009 Sep;146(5):467-78
references: 19466978
references: Nat Genet. 1997 Sep;17(1):25-31
references: 9288094
references: Cell. 2010 Mar 19;140(6):821-32
references: 20303873
references: Mamm Genome. 2000 Jun;11(6):428-35
references: 10818206
references: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7803-8
references: 18511561
references: Immunity. 2006 Mar;24(3):317-27
references: 16546100
references: Eur J Pediatr. 2008 Jun;167(6):695-6
references: 17588171
references: Nature. 2006 Mar 9;440(7081):228-32
references: 16407890
references: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9982-7
references: 16785446
references: Mol Cell. 2003 Mar;11(3):591-604
references: 12667444
references: Nephrol Dial Transplant. 2009 Feb;24(2):676-8
references: 19033248
references: Cell. 2010 Mar 19;140(6):784-90
references: 20303869
references: Clin Rheumatol. 2010 Feb;29(2):209-10
references: 19774408
references: Am J Med. 1967 Aug;43(2):227-53
references: 5340644
references: Arthritis Rheum. 2004 Nov;50(11):3679-89
references: 15529356
references: Arthritis Rheum. 2009 Jun;60(6):1862-6
references: 19479871
references: Cell Death Differ. 2006 Feb;13(2):236-49
references: 16037825
references: Blood. 2002 Aug 1;100(3):774-7
references: 12130485
references: Joint Bone Spine. 2008 Jul;75(4):504-5
references: 18541452
references: Cell. 1997 Aug 22;90(4):797-807
references: 9288758