Inflammation in mice ectopically expressing human PAPA syndrome-associated PSTPIP1 A230T mutant proteins.
ABSTRACT Pyogenic Arthritis, Pyoderma Gangrenosum and Acne Syndrome (PAPA syndrome) is an autoinflammatory disease caused by aberrant production of the proinflammatory cytokine interleukin-1. Mutations in the gene encoding proline serine threonine phosphatase interacting protein-1 (PSTPIP1) have been linked to PAPA syndrome. PSTPIP1 is an adaptor protein that interacts with PYRIN, the protein encoded by the Mediterranean Fever (MEFV) gene whose mutations cause Familial Mediterranean Fever (FMF). However, the pathophysiological function of PSTPIP1 remains to be elucidated. We have generated mouse strains that either are PSTPIP1 deficient or ectopically express mutant PSTPIP1. Rusults from analyzing these mice suggested that PSTPIP1 is not an essential regulator of the Nlrp3, Aim2 or Nlrc4 inflammasomes. Although common features of human PAPA syndrome such as pyogenic arthritis and skin inflammation were not recapitulated in the mouse model, ectopic expression of the mutant but not the wild type PSTPIP1 in mice lead to partial embryonic lethality, growth retardation and elevated level of circulating proinflammatory cytokines.
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ABSTRACT: Multiple clinical trials have shown that the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins have anti-inflammatory effects. However, the underlying molecular mechanism remains unclear. The proinflammatory cytokine interleukin-1β (IL-1β) is synthesized as a non-active precursor. The 31-kDa pro-IL-1β is processed into the 17-kDa active form by caspase-1-activating inflammasomes. Here, we report a novel signaling pathway induced by statins which leads to processing of pro-IL-1β into an intermediate 28-kDa form. This statin-induced IL-1β processing is independent of caspase-1- activating inflammasomes. The 28-kDa form of IL-1β cannot activate IL-1RI to signal inflammatory responses. Instead, it interferes with mature IL-1β signaling through IL-1R and therefore may dampen inflammatory responses initiated by mature IL-1β. These results may provide new clues to explain the anti-inflammatory effects of statins.Journal of Biological Chemistry 04/2014; DOI:10.1074/jbc.M114.571505 · 4.60 Impact Factor
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ABSTRACT: Proline‐serine‐threonine phosphatase interacting protein 1 (PSTPIP1) is an adaptor protein associated with the cytoskeleton that is mainly expressed in hematopoietic cells. Mutations in PSTPIP1 cause the rare autoinflammatory disease called pyogenic arthritis, pyoderma gangrenosum, and acne. We carried out this study to further our knowledge on PSTPIP1 function in T cells, particularly in relation to the phosphatase lymphoid phosphatase (LYP), which is involved in several autoimmune diseases. LYP–PSTPIP1 binding occurs through the C‐terminal homology domain of LYP and the F‐BAR domain of PSTPIP1. PSTPIP1 inhibits T‐cell activation upon T‐cell receptor (TCR) and CD28 engagement, regardless of CD2 costimulation. This function of PSTPIP1 depends on the presence of an intact SH3 domain rather than on the F‐BAR domain, indicating that ligands of the F‐BAR domain, such as the PEST phosphatases LYP and PTP‐PEST, are not critical for its negative regulatory role in TCR signaling. Additionally, PSTPIP1 mutations that cause the pyogenic arthritis, pyoderma gangrenosum and acne syndrome do not affect PSTPIP1 function in T‐cell activation through the TCR.FEBS Journal 09/2014; 281(17). DOI:10.1111/febs.12912 · 3.99 Impact Factor
Article: [Inflammasomes in human diseases.][Show abstract] [Hide abstract]
ABSTRACT: The understanding of the innate immunity, the first line of the host defence, was significantly modified following the sequential discovery of innate immune receptors such as the Toll-like receptors (TLRs) and the NOD-like receptors (NLRs). In response to recognition of microbial patterns or danger signals, some NLRs assemble a multimolecular platform termed as the inflammasome. Inflammasome assembly leads to the activation of the proinflammatory caspase-1. Consequently, an inflammatory immune response is mounted along with a programmed cell death, called pyroptosis. This review summarizes recent advances in the knowledge of the inflammasome and its role in auto-inflammatory diseases, autoimmune diseases, and most common metabolic, cardiovascular or rheumatic diseases.