Journal article
Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice
Proceedings of the National Academy of Sciences - PNAS, Vol.111(3), pp.1072-1077
01/21/2014
DOI: 10.1073/pnas.1318685111
PMCID: PMC3903222
PMID: 24395802
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.
Details
- Title: Subtitle
- Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice
- Creators
- Suzanne L Cassel - Inflammation ProgramJohn R Janczy - Inflammation ProgramXinyu Bing - Department of PediatricsShruti P Wilson - Department of Internal MedicineAlicia K Olivier - Department of PathologyJesse E Otero - Department of OrthopedicsYoichiro Iwakura - Research Institute for Biomedical SciencesDmitry M Shayakhmetov - Division of Medical Genetics, Department of MedicineAlexander G Bassuk - Department of PediatricsYousef Abu-Amer - Department of Orthopedics, Washington University School of Medicine, St. LouisKim A Brogden - Dows Institute for Dental Research and Department of Periodontics, College of Dentistry, andTrudy L Burns - Department of PediatricsFayyaz S Sutterwala - Inflammation ProgramPolly J Ferguson - Department of Pediatrics
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.111(3), pp.1072-1077
- DOI
- 10.1073/pnas.1318685111
- PMID
- 24395802
- PMCID
- PMC3903222
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Alternative title
- Inflammasome-independent IL-1β drives CMO disease
- Language
- English
- Date published
- 01/21/2014
- Academic Unit
- Neurology; Critical Care; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Orthopedics and Rehabilitation; Fraternal Order of Eagles Diabetes Research Center; Rheumatology, Allergy, and Immunology; Neurology (Pediatrics); Periodontics
- Record Identifier
- 9984013205002771
Metrics
18 Record Views