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.
"A deregulation of caspase-1 activation and an increased production of IL-1b as well as tumor necrosis factor in peripheral blood mononuclear cells have been reported (Shoham et al., 2003; Cortis et al., 2004). PSTPIP1 mutants have been shown to induce proIL-1b processing by caspase-1 (Yu et al., 2007; Wang et al., 2013) and Anakinra has been shown to be effective in the control of inflammatory manifestations in certain patients (Dierselhuis et al., 2005; Brenner et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: During the past years, significant progress in the understanding of the complexity, regulation, and relevance of innate immune responses underlying several inflammatory conditions with neutrophilic skin involvement has been made. These diseases belong to the novel class of autoinflammatory diseases, and several are caused by mutations in genes regulating the function of innate immune complexes, termed inflammasomes, leading to enhanced secretion of the proinflammatory cytokine IL-1β. Consequently, targeting of IL-1β has proven successful in the treatment of these diseases, and the identification of related pathogenic mechanisms in other more common skin diseases characterized by autoinflammation and neutrophilic tissue damage also provides extended opportunities for therapy by interfering with IL-1 signaling.Journal of Investigative Dermatology advance online publication, 6 March 2014; doi:10.1038/jid.2014.76.
[Show abstract][Hide abstract] ABSTRACT: Human pyrin with gain-of-function mutations in its B30.2/SPRY domain causes the autoinflammatory disease familial Mediterranean fever by assembling an ASC-dependent inflammasome that activates caspase-1. Wildtype human pyrin can also form an inflammasome complex with ASC after engagement by autoinflammatory PSTPIP1 mutants. How the pyrin inflammasome is activated in the absence of disease-associated mutations is not yet known. We report here that ribotoxic stress triggers the assembly of the human pyrin inflammasome leading to ASC oligomerization and caspase-1 activation in THP-1 macrophages, and in a 293T cell line stably reconstituted with components of the pyrin inflammasome. Knockdown of pyrin and selective inhibition of p38 mitogen-activated protein kinase (MAPK) greatly attenuated caspase-1 activation by ribotoxic stress, while expression of the conditional mutant ΔMEKK3:ER* allowed activation of caspase-1 without ribotoxic stress. Disruption of microtubules by colchicine also inhibited pyrin inflammasome activation by ribotoxic stress. Together, our results indicate that ribotoxic stress activates the human pyrin inflammasome through a mechanism that requires p38 MAPK signaling and microtubule stability.
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of monogenic autoinflammatory diseases converges on the presence of exaggerated immune responses that are triggered through activation of altered pattern recognition receptor (PRR) pathways and result in cytokine/chemokine amplification loops and the inflammatory clinical phenotype seen in autoinflammatory patients. The PRR response can be triggered by accumulation of metabolites, by mutations in sensors leading to their constitutive overactivation, or by mutations in mediator cytokine pathways that lead to amplification and/or inability to downregulate an inflammatory response in hematopoietic and/or nonhematopoietic cells. The study of the pathogenesis of sterile inflammation in patients with autoinflammatory syndromes continues to uncover novel inflammatory pathways.
Rheumatic diseases clinics of North America 11/2013; 39(4):701-34. DOI:10.1016/j.rdc.2013.08.001 · 2.69 Impact Factor
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