Mutation of mouse Mayp/Pstpip2 causes a macrophage autoinflammatory disease

Abstract

IntroductionAutoinflammatory diseases are systemic conditions involving apparently unprovoked inflammation in the absence of autoantibody-and antigenic-specific T cells. A significant proportion of these diseases is caused by single gene mutations. Furthermore, the mutated gene remains to be discovered in a number of Mendelian inherited autoinflammatory diseases. 1 Identifying the genes involved is a first step toward elucidating the pathways involved in the inflammatory processes underlying these diseases. Among the genes recently identified as causal is the gene encoding the TNF receptor, which has long been recognized for its role in inflammation and immunity. TNF receptor-associated periodic syndrome (TRAPS) is caused by mutations in the extracellular domain of the 55-kDa TNF receptor that lead to a dominantly inherited periodic fever. 2 Leukocytes from some, but not all, of these patients have increased membrane TNFRS1A and impaired receptor ectodomain cleavage on in vitro stimulation, consistent with a deficiency in a normal negative homeostatic process. 3 Two autoinflammatory periodic fever syndromes in which the mutated gene has been identified recently point to a common pathway. 4 Familial Mediterranean fever (FMF) is an autosomal recessive disorder resulting from mutations in the gene encoding pyrin, which normally inhibits pro-IL-1␤ cytokine processing to the active form. It has recently been shown that mutations in the structural gene encoding Pombe Cdc15 homology (PCH) family protein, proline serine threonine phosphatase-interacting protein 1/CD2 binding protein 1 (PSTPIP1/ CD2BP1), 5 lead to an autosomal-dominant autoinflammatory disease called pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. 6 These mutations lead to decreased binding of PSTPIP1 to a protein tyrosine phosphatase, PTP-PEST, that specifically dephosphorylates PSTPIP1. 6,7 Subsequent studies by Shoham et al 8 showed that pyrin, the protein involved in FMF, interacts with PSTPIP1, thus establishing an important biochemical link between the proteins involved in these 2 diseases. Clearly, identification of the genes mutated in autoinflammatory diseases such as TRAPS, FMF, and PAPA, coupled with increased understanding of the functions of the proteins encoded by them, promises to greatly increase our knowledge of the mechanisms that mediate leukocyte inflammatory responses.PCH proteins constitute an extensive protein family involved in the regulation of actin polymerization and actin-based processes, including membrane ruffling, formation of filopodia, cell adhesion, and cytokinesis. [9][10][11][12][13][14][15] The PCH protein, macrophage actin-associated tyrosine phosphorylated protein (MAYP), 11 closely related to PSTPIP1 and also known as PSTPIP2, 12 is expressed in macrophages and macrophage-containing tissues. 11 Like that of PSTPIP1 and the other PCH family members, its domain organization includes an amino-terminal Fes-CIP4 homology (FCH) domain For personal use only. on May 9, 2018. by guest www.bloodjournal.or...

Critical role for inflammasome-independent IL-1β production in osteomyelitis

“…S1). Our findings demonstrating normal T-cell responses and activation in PSTPIP2-deficient mice are in agreement with an earlier report showing that osteomyelitic disease ensues in the absence of T cells in a separate Pstpip2 genetic mouse model (Pstpip2 lupo mice) (5). Collectively, these results suggest that osteolytic bone disease in Pstpip2 cmo mice may primarily be linked to dysregulated innate immune signaling.…”

“…However, the roles of specific inflammatory pathways and immune cell networks in disease pathogenesis remain to be fully characterized for most bone disorders. Recently, missense mutations in the proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) were shown to cause a bone disease in mice that is characterized by osteomyelitis and bone deformity (4)(5)(6). In particular, the chronic multifocal osteomyelitis (cmo) mouse that carries a homozygous L98P missense mutation in PSTPIP2 (referred to as Pstpip2 cmo mice) develops a chronic autoinflammatory disease that resembles CRMO in humans (7).…”

Inflammatory caspases and inflammasomes: master switches of inflammation

“…136 Moreover, mutations in a mouse-related protein PSTPIP2 causes a macrophage autoinflammatory syndrome, further delineating the importance of Pyrin and inflammasome regulation in autoinflammatory disorders. 137 …”

PSTPIP2 deficiency in mice causes osteopenia and increased differentiation of multipotent myeloid precursors into osteoclasts

“…[6][7][8][9] Proline serine threonine phosphatase-interacting protein 2 (PST-PIP2), also known as macrophage F-actin-associated and tyrosine phosphorylated protein (MAYP), is a Fes CIP4 homology domain (FCH) and Bin/Amphiphysin/Rvs (BAR; F-BAR) protein, predominantly expressed in the myeloid lineage. 10 It is rapidly tyrosine phosphorylated after activation of CSF-1 receptor (CSF-1R), [10][11][12][13][14] and exhibits reduced phosphorylation in mast cells in which c-Kit is inhibited. 12 The mouse Pstpip2 missense mutations, chronic multifocal osteomyelitis (cmo), L98P (Pstpip2 cmo/cmo ), and Lupo I282N (Pstpip2 Lupo/Lupo ) lead to similar autoinflammatory diseases, both characterized by splenomegaly, skin necrosis, and aseptic osteomyelitis.…”

“…11,[14][15][16][17] The mutations result in complete (cmo) or partial (Lupo) PSTPIP2 protein deficiency, indicating that PSTPIP2 has anti-inflammatory activity. 11,14 Histologic studies of the cmo mice showed osteoclast-mediated bone resorption at sites of inflammation in caudal vertebrae, 15,17 and cultured cmo bone marrow cells exhibited increased vitamin D 3 -induced osteoclastogenic responses. 17 However, the molecular bases of these phenotypes were not elucidated.…”