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Blood, 17 September 2009, Vol. 114, No. 12, pp. 2497-2505. Prepublished online as a Blood First Edition Paper on July 16, 2009; DOI 10.1182/blood-2009-02-204925. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2009-02-204925v1 114/12/2497    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Chitu, V. Articles by Stanley, E. R. PubMed PubMed Citation Articles by Chitu, V. Articles by Stanley, E. R. Related Collections Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice Violeta Chitu1, Polly J. Ferguson2, Rosalie de Bruijn1, Annette J. Schlueter3, Luis A. Ochoa2, Thomas J. Waldschmidt3, Yee-Guide Yeung1, and E. Richard Stanley1 1 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY; and Departments of 2 Pediatrics and 3 Pathology, Carver College of Medicine, University of Iowa, Iowa City 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 Pstpip2cmo/cmo mice have increased circulating levels of macrophage inflammatory protein 1- 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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