An inherited mutation in NLRC4 causes autoinflammation in human and mice.
Autoinflammatory syndromes cause sterile inflammation in the absence of any signs of autoimmune responses. Familial cold autoinflammatory syndrome (FCAS) is characterized by intermittent episodes of rash, arthralgia, and fever after exposure to cold stimuli. We have identified a missense mutation in the NLRC4 gene in patients with FCAS. NLRC4 has been known as a crucial sensor for several Gram-negative intracellular bacteria. The mutation in NLRC4 in FCAS patients promoted the formation of NLRC4-containing inflammasomes that cleave procaspase-1 and increase production of IL-1β. Transgenic mice that expressed mutant Nlrc4 under the invariant chain promoter developed dermatitis and arthritis. Inflammation within tissues depended on IL-1β-mediated production of IL-17A from neutrophils but not from T cells. Our findings reveal a previously unrecognized link between NLRC4 and a hereditary autoinflammatory disease and highlight the importance of NLRC4 not only in the innate immune response to bacterial infections but also in the genesis of inflammatory diseases.
Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima 770-8503, Japan.
Akiko
A
Kitamura
Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima 770-8503, Japan.
Yuki
Y
Sasaki
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Chuou-ku, Kobe 650-0047, Japan.
Takaya
T
Abe
Department of Pediatrics, Teikyo University Mizonokuchi Hospital, Kawasaki, Kanagawa 213-8507, Japan.
Hirotsugu
H
Kano
Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima 770-8503, Japan JST, CREST, Tokyo 102-0076, Japan yasutomo@tokushima-u.ac.jp.
Koji
K
Yasutomo
D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D015153:Blotting, Western; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009504:Neutrophils / Q000378:metabolism; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D020381:Interleukin-17; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; C435692:NLRC4 protein, human; D020170:Caspase 1