Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

Abstract

Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of IL-1β. We studied a family with dominantly inherited autoinflammatory disease characterised by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. Disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The clinical distinction from FMF, also caused by MEFV mutation, was due to loss of a 14-3-3 binding motif at phosphorylated S242. This interaction represents a guard regulating pyrin activation, which is downstream of bacterial effectors that trigger the pyrin inflammasome. S242R mutation recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND). This unique disease provides evidence that a guard mechanism, originally identified in plant innate immunity, also exists in humans.3 Main textAutoinflammatory diseases are characterized by recurrent episodes of fever with systemic and organ-specific inflammation, as well as uncontrolled activation of the innate immune response in the apparent absence of an infectious trigger(1). Familial Mediterranean fever (FMF, OMIM ID: 249100) is the most common of these monogenic diseases, characterized by short (24-72 h) episodes of fever associated with serositis, progressing to amyloidosis if untreated(2). FMF is an autosomal recessive disease caused by mutations in both alleles of the MEFV (MEditerranean FeVer) locus, which encodes the protein pyrin(3). Normally, pyrin functions as a link between intracellular pathogen sensing and activation of the inflammasome, allowing the production of inflammatory mediators during infection. As a potent checkpoint for the initiation of inflammation, the mechanisms of pyrin regulation are critical, and yet still poorly understood.We studied a three-generation Belgian family of 22 individuals, of whom 12 developed autoinflammatory disease (Figure 1a). The disease was characterized by neutrophilic dermatosis, childhood-onset recurrent episodes of fever lasting several weeks, increased levels of acute-phase reactants, arthralgia and myalgia/myositis (Figure 1b). The neutrophilic dermatosis comprised a spectrum of clinical manifestations including severe acne, sterile skin abscesses, pyoderma gangrenosum and neutrophilic small vessel vasculitis (Figure 1c,d).Pathological examination of affected skin showed a dense, predominantly neutrophilic, vascular, perivascular and interstitial infiltrate (Figure 1d). Serum cytokine analysis revealed elevated inflammatory mediators such as IL-1β, IL-6 and TNFα, and cytokines induced by inflammation such as IL-1Ra (Figure 1e, Figure S1a unlike some of the more typical FMF variants, that naturally occur in other species(7). Despite the association of MEFV mutations w...

Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation

“…Importantly, the B30.2 domain is absent in the murine Pyrin ortholog, which prompted us to characterize regulation mechanisms of Pyrin activation in peripheral blood mononuclear cells (PBMCs) of healthy donors in parallel with studies in murine bone marrow-derived macrophages (BMDMs). As reported (14,15), TcdB activated the Pyrin inflammasome in our studies ( Fig. S1 A and B).…”

“…Dephosphorylation of Pyrin's intermediate linker domain was recently shown to be required for TcdA-and TcdB-induced inflammasome activation (14,15,19), and introduction of FMF mutations in the B30.2 domain of ectopically expressed Pyrin did not interfere with this process (15). In agreement with these reports, we showed that endogenous Pyrin was not constitutively active in FMF PBMCs but was engaged only after TcdA stimulation or C. difficile infection ( Fig.…”

“…The Pyrin inflammasome responds to infection with Burkholderia cenocepacia (12,13) and the Rho GTPasetargeting toxins Clostridium botulinum toxin C3 and C. difficile cytotoxin B (TcdB) in mouse macrophages (13)(14)(15). Importantly, the B30.2 domain is absent in the murine Pyrin ortholog, which prompted us to characterize regulation mechanisms of Pyrin activation in peripheral blood mononuclear cells (PBMCs) of healthy donors in parallel with studies in murine bone marrow-derived macrophages (BMDMs).…”

IL-1β and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1α or Caspase-8 in a Mouse Model of Familial Mediterranean Fever

“…49,50 FMF-associated mutations in the B30.2 domain inhibit the interaction between pyrin and protein kinase N1, and reduce the inhibitory control on pyrin activation. 49 Our work, along with the earlier-mentioned findings, define the upstream molecular mechanisms involved in IL-1b release during FMF pathogenesis.…”

Molecular Diagnosis Experience in Familial Mediterranean Fever: The Most Frequent Mutations in the MEFV Gene

“…MEFV geni üzerinde bugüne kadar tanımlanmış olan mutasyonlar Tablo 1'de verilmiştir (5). MEFV geninde meydana gelen mutasyonlar, pyrin ekspresyonunu azaltır ve interlökin (IL)-1β'yı aktive eden kaspaz-1 enflamasyon kontrol mekanizmasındaki işlevini yerine getiremediğinden uyarılmış olan enflamasyon durdurulamaz (6). Pyrin proteininin IL-1β işlenmesini engellemesi ve makrofaj apoptozuna izin vermesi, fonksiyonel olarak antienflamatuvar bir molekül olduğunu göstermektedir.…”