title: Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice.
abstract: Chronic recurrent multifocal osteomyelitis (CRMO) is a human autoinflammatory disorder that primarily affects bone. Missense mutation (L98P) of proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) in mice leads to a disease that is phenotypically similar to CRMO called chronic multifocal osteomyelitis (cmo). Here we show that deficiency of IL-1RI in cmo mice resulted in a significant reduction in the time to onset of disease as well as the degree of bone pathology. Additionally, the proinflammatory cytokine IL-1β, but not IL-1α, played a critical role in the pathology observed in cmo mice. In contrast, disease in cmo mice was found to be independent of the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome as well as caspase-1. Neutrophils, but not bone marrow-derived macrophages, from cmo mice secreted increased IL-1β in response to ATP, silica, and Pseudomonas aeruginosa compared with neutrophils from WT mice. This aberrant neutrophil response was sensitive to inhibition by serine protease inhibitors. These results demonstrate an inflammasome-independent role for IL-1β in disease progression of cmo and implicate neutrophils and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting IL-1RI or IL-1β as a therapeutic strategy in CRMO.
authors.affiliation: Inflammation Program, Department of Internal Medicine, Graduate Program in Immunology, Department of Pediatrics, Department of Pathology, Department of Orthopedics, Dows Institute for Dental Research and Department of Periodontics, College of Dentistry, and Department of Epidemiology, University of Iowa, Iowa City, IA 52242.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Cassel
authors.forename: John R
authors.initials: JR
authors.lastname: Janczy
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bing
authors.forename: Shruti P
authors.initials: SP
authors.lastname: Wilson
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Otero
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Dmitry M
authors.initials: DM
authors.lastname: Shayakhmetov
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu-Amer
authors.forename: Kim A
authors.initials: KA
authors.lastname: Brogden
authors.forename: Trudy L
authors.initials: TL
authors.lastname: Burns
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Ferguson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D020125:Mutation, Missense; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D010019:Osteomyelitis / Q000235:genetics / Q000276:immunology*; D017434:Protein Structure, Tertiary; D017472:Receptors, Interleukin-1 / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C486383:Pstpip2 protein, mouse; D017472:Receptors, Interleukin-1
keywords: chronic osteomyelitis; innate immunity