title: Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice.
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-alpha 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.
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. vchitu@aecom.yu.edu
authors.forename: Violeta
authors.initials: V
authors.lastname: Chitu
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Ferguson
authors.forename: Rosalie
authors.initials: R
authors.lastname: de Bruijn
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Schlueter
authors.forename: Luis A
authors.initials: LA
authors.lastname: Ochoa
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Waldschmidt
authors.forename: Yee-Guide
authors.initials: YG
authors.lastname: Yeung
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D054405:Chemokine CCL3 / Q000378:metabolism; D002908:Chronic Disease; D003598:Cytoskeletal Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000473:pathology; D007113:Immunity, Innate / Q000502:physiology; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism; D010019:Osteomyelitis / Q000276:immunology* / Q000473:pathology; D010766:Phosphorylation; D012190:Retroviridae / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013864:Thioglycolates / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054405:Chemokine CCL3; D003598:Cytoskeletal Proteins; D015850:Interleukin-6; C486383:Pstpip2 protein, mouse; D050794:STAT1 Transcription Factor; D013864:Thioglycolates; D016173:Macrophage Colony-Stimulating Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3