Journal article
Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice
Blood, Vol.114(12), pp.2497-2505
Phagocytes, Granulocytes, and Myelopoiesis
09/17/2009
DOI: 10.1182/blood-2009-02-204925
PMCID: PMC2746474
PMID: 19608749
Abstract
The mouse
Lupo
(I282N) mutation in proline-serine-threonine phosphatase–interacting protein 2 (PSTPIP2) leads to reduced expression of PSTPIP2 that is associated with a macrophage-mediated autoinflammatory disease. Another mutation in PSTPIP2, L98P, termed
chronic multifocal osteomyelits (cmo)
, leads to a disease in mice that resembles chronic recurrent multifocal osteomyelits in humans. The cellular basis of
cmo
disease was investigated.
cmo
disease develops independently of lymphocytes and is cured by bone marrow transplantation. Macrophages, mast cells, and osteoclasts from
cmo
mice fail to express detectable PSTPIP2 protein. Asymptomatic
Pstpip2
cmo/cmo
mice have increased circulating levels of macrophage inflammatory protein 1-α and interleukin-6, and their macrophages exhibit increased production of these inflammatory mediators, which is normalized by retroviral expression of wild-type PSTPIP2. Spleens of asymptomatic
cmo
mice contain increased numbers of macrophage precursors, and
cmo
mice mobilize more macrophage precursors in response to a sterile inflammatory stimulus. Signal transducer and activator of transcription 1 is elevated in
cmo
splenic macrophages, which also exhibit increased colony-stimulating factor-1–stimulated proliferation and increased extracellular signal-regulated kinase 1/2 phosphorylation. PSTPIP2 overexpression in macrophages leads to the opposite phenotype. Thus, PSTPIP2 deficiency causes both an expansion of macrophage progenitors and increased responsiveness of mature macrophages to activating stimuli, which together prime the organism for exaggerated and sustained responses leading to autoinflammatory disease.
Details
- Title: Subtitle
- Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice
- Creators
- Violeta Chitu - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY; andPolly J Ferguson - Departments ofRosalie de Bruijn - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY; andAnnette J Schlueter - Pathology, Carver College of Medicine, University of Iowa, Iowa CityLuis A Ochoa - Departments ofThomas J Waldschmidt - Pathology, Carver College of Medicine, University of Iowa, Iowa CityYee-Guide Yeung - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY; andE. Richard Stanley - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY; and
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.114(12), pp.2497-2505
- Publisher
- American Society of Hematology; Washington, DC
- Series
- Phagocytes, Granulocytes, and Myelopoiesis
- DOI
- 10.1182/blood-2009-02-204925
- PMID
- 19608749
- PMCID
- PMC2746474
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Grant note
- RO1 CA25604; K01AR 054486 / National Institutes of Health
- Language
- English
- Date published
- 09/17/2009
- Academic Unit
- Cardiology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Rheumatology, Allergy, and Immunology
- Record Identifier
- 9984047647702771
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