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.
"In whole animals, the anti-inflammatory role of PSTPIP2 was shown in mouse model studies [134,135]. Mice with PSTPIP2 mutations that cause reduced expression levels (cmo and lupo) leads to fatal autoimmune disease due in part to hyperactivation of macrophages . "
[Show abstract][Hide abstract] ABSTRACT: Eukaryotic cells have complicated membrane systems. The outermost plasma membrane contains various substructures, such as invaginations and protrusions, which are involved in endocytosis and cell migration. Moreover, the intracellular membrane compartments, such as autophagosomes and endosomes, are essential for cellular viability. The Bin-Amphiphysin-Rvs167 (BAR) domain superfamily proteins are important players in membrane remodeling through their structurally determined membrane binding surfaces. A variety of BAR domain superfamily proteins exist, and each family member appears to be involved in the formation of certain subcellular structures or intracellular membrane compartments. Most of the BAR domain superfamily proteins contain SH3 domains, which bind to the membrane scission molecule, dynamin, as well as the actin regulatory WASP/WAVE proteins and several signal transduction molecules, providing possible links between the membrane and the cytoskeleton or other machineries. In this review, we summarize the current information about each BAR superfamily protein with an SH3 domain(s). The involvement of BAR domain superfamily proteins in various diseases is also discussed.
"Point mutations of PSTPIP1 in humans are found in PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum and acne), where there is severely reduced binding between the mutant protein and PTP-PEST . Another example of inflammatory disease can be found in mice possessing a point mutation in the MAYP/PSTPIP2 protein   . These mice exhibit a phenotype similar to chronic recurrent multifocal osteomyelitis , with osteolysis and necrosis in paws of the ears. "
[Show abstract][Hide abstract] ABSTRACT: Remodeling of the membrane and cytoskeleton is involved in a wide range of normal and pathologic cellular function. These are complex, highly-coordinated biochemical and biophysical processes involving dozens of proteins. Serving as a scaffold for a variety of proteins and possessing a domain that interacts with plasma membranes, the BAR family of proteins contribute to a range of cellular functions characterized by membrane and cytoskeletal remodeling. There are several subgroups of BAR proteins: BAR, N-BAR, I-BAR, and F-BAR. They differ in their ability to induce angles of membrane curvature and in their recruitment of effector proteins. Evidence is accumulating that BAR proteins contribute to cancer cell invasion, T cell trafficking, phagocytosis, and platelet production. In this review, we discuss the physiological function of BAR proteins and discuss how they contribute to blood and cancer disorders.
International Journal of Biochemistry and Molecular Biology 07/2012; 3(2):198-208.
"The first part of this unit provides protocols for measuring the abundance and growth of macrophage precursors in agar cultures (Basic Protocol 1) and the proliferation of isolated mature macrophages in vitro, either by direct cell counting (Basic Protocol 2) or by DNA measurement (Basic Protocol 3). These methods can be applied to macrophage cell lines (Yu et al., 2008; Chitu et al., 2009) as well as to many primary macrophage populations including bronchoalveolar lavage cells, liver Kupffer cells, bone-marrow-derived macrophages, splenocyte-derived macrophages, and peritoneal exudate or resident peritoneal macrophages (Stanley et al., 1978; Chen et al., 1979; Chitu et al., 2009). In addition, we describe methods for the immunohistochemical identification of macrophages (Basic Protocol 4) and BrdU and Iba1 double labeling of microglia for determination of microglial growth in vivo (Basic Protocol 5). "
[Show abstract][Hide abstract] ABSTRACT: This unit provides protocols for measuring the abundance and growth of macrophage precursors in agar cultures and the proliferation of isolated mature macrophages in vitro, by either direct cell counting or by DNA measurement. Methods for the immunohistochemical identification of macrophages and the determination of their proliferative status in vivo by immunofluorescence are also included. It also describes methods for characterization of macrophage differentiation through the immunofluorescence analysis of cell-surface expression of CSF-1 receptor.
Current protocols in immunology / edited by John E. Coligan ... [et al.] 02/2011; Chapter 14:Unit 14.20.1-26. DOI:10.1002/0471142735.im1420s92
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