Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome

Jamilloux, Yvan; Lefeuvre, Lucie; Magnotti, Flora; Martin, Amandine; Benezech, Sarah; Allatif, Omran; Penel‐Page, Mathilde; Hentgen, Véronique; Sève, P.; Gerfaud‐Valentin, Mathieu; Duquesne, Agnès; Desjonquères, Marine; Laurent, Audrey; Remy-Piccolo, Vanessa; Cimaz, Rolando; Cantarini, Luca; Bourdonnay, Emilie; Walzer, Thierry; Py, Bénédicte F.; Belot, Alexandre; Henry, Thomas

doi:10.1093/rheumatology/kex373

Cited by 65 publications

(51 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This result suggests that UCN‐01 triggers inflammasome activation in FMF patient monocytes. As previously described (Van Gorp et al , ), we did not observe any difference in IL‐1β release in response to engagement of the NLRP3 inflammasome by LPS + ATP () or of the NLRC4 inflammasome (Jamilloux et al , ). Furthermore, LPS + staurosporine treatment did not lead to differential TNF secretion between monocytes from HD and FMF patients (Fig C), indicating that the differing response to PKC inhibitors between HD and FMF patients is specific to inflammasome activation.…”

Section: Resultssupporting

confidence: 83%

“…The difference in cell death was specific to PKC inhibitors since NLRP3 inflammasome activation by LPS + nigericin (Mariathasan et al , ) triggered propidium iodide influx with similar kinetics in monocytes from HD and FMF patients (Fig G–I and ). Importantly, the UCN‐01‐mediated fast cell death was observed in the absence of LPS treatment, indicating that the Pyrin inflammasome does not require TLR‐mediated priming, as previously demonstrated following C. difficile toxin treatment (Van Gorp et al , ; Jamilloux et al , ).…”

Section: Resultssupporting

confidence: 70%

“…As seen with staurosporine, the difference in IL‐1β response between monocytes from HD and FMF patients was conserved over a large range of concentrations of UCN‐01 (). The hyper‐responsiveness of FMF monocytes to PKC superfamily inhibitors thus differs from their hyper‐responsiveness to Clostridioides difficile toxin TcdB, which was observed only at low doses of TcdB (Jamilloux et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…The links between MEFV mutations, the dysfunctional Pyrin inflammasome, and FMF remain poorly understood. In contrast to the typical gain‐of‐function mutations of NLRP3 or NLRC4 observed in cryopyrin‐associated periodic syndromes and NLRC4‐associated syndromes, MEFV mutations do not lead to a spontaneous activation of the Pyrin inflammasome in the absence of a specific stimulus (Van Gorp et al , ; Jamilloux et al , ). We have previously shown that MEFV mutations lower the activation threshold of the Pyrin inflammasome in response to a Pyrin inflammasome stimulus (Jamilloux et al , ).…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients

et al. 2019

Self Cite

View full text Add to dashboard Cite

Familial Mediterranean fever (FMF) is the most frequent hereditary systemic autoinflammatory syndrome. FMF is usually caused by biallelic mutations in the MEFV gene, encoding Pyrin. Conclusive genetic evidence lacks for about 30% of patients diagnosed with clinical FMF. Pyrin is an inflammasome sensor maintained inactive by two kinases (PKN1/2). The consequences of MEFV mutations on inflammasome activation are still poorly understood. Here, we demonstrate that PKC superfamily inhibitors trigger inflammasome activation in monocytes from FMF patients while they trigger a delayed apoptosis in monocytes from healthy donors. The expression of the pathogenic p.M694V MEFV allele is necessary and sufficient for PKC inhibitors (or mutations precluding Pyrin phosphorylation) to trigger caspase‐1‐ and gasdermin D‐mediated pyroptosis. In line with colchicine efficacy in patients, colchicine fully blocks this response in FMF patients’ monocytes. These results indicate that Pyrin inflammasome activation is solely controlled by Pyrin (de)phosphorylation in FMF patients while a second control mechanism restricts its activation in healthy donors/non‐FMF patients. This study paves the way toward a functional characterization of MEFV variants and a functional test to diagnose FMF.

show abstract

Section: Resultssupporting

confidence: 83%

Section: Resultssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Des conditions identiques semblent exister pour l'assemblage de l'inflammasome NLRP3 dans d'autres types cellulaires, moins étudiés que les macrophages, dont les monocytes, les mastocytes ou les neutrophiles. Néanmoins, dans les monocytes humains, le signal de priming peut suffire à l'assemblage de l'inflammasome, dans certaines conditions [13,14]. Le priming de NLRP3 se produit à la suite de l'activation par leurs ligands de récepteurs, dont les TLR (Toll-like receptors), NOD2 (nucleotidebinding oligomerization domain 2), ou RAGE (receptor for advanced glycation end products), pour les PAMP/DAMP, ou, pour les cytokines, REVUES À la suite du priming, NLRP3 devient compétent pour être activé.…”

Section: Les Voies De Signalisation Qui Contrôlent L'assemblage De L'unclassified

NLRP3, un inflammasome sous contrôle

Groslambert

2018

Med Sci (Paris)

View full text Add to dashboard Cite

> La réponse immunitaire innée protège l'organisme par la détection rapide des agents pathogènes et des lésions via des récepteurs spéciali-sés, dont NLRP3. Celui-ci assemble un inflammasome, un complexe cytosolique de signalisation qui active la caspase-1, contrôle la libération de cytokines et de facteurs inflammatoires produits dans le cytosol comme les interleukines 1 / . Les pathologies inflammatoires associées à NLRP3, dont la goutte, révèlent la nécessité d'un contrôle étroit de son activité. Cette revue présente les avancées sur la signalisation du priming (ou amorçage) du complexe puis de son activation avec une attention particulière sur le rôle des modifications post-traductionnelles de NLRP3. < cytokines et d'autres facteurs intracellulaires pro-inflammatoires dont l'IL-1 La mort par pyroptose de cellules infectées permet d'éliminer en parallèle les niches de réplication des pathogènes intracellulaires. La structure des inflammasomes dits non-canoniques, associés à la caspase-11, ou 4 et 5 chez l'homme, reste mal connue. Les inflammasomes canoniques, qui sont eux, associés à la caspase-1, sont assemblés par des récepteurs cytosoliques de la famille des NLR (nucleotide-binding domain leucin-rich repeat) ou ALR (Aim2-like receptors). Ces récepteurs s'oligomérisent pour former une plateforme de nucléation pour des filaments formés par la protéine adaptatrice ASC (apoptosis-associated speck-like protein containing a CARD domain, aussi appelé PYCARD, CARD5, TMS1, Q9ULZ3), dont la surface permet, à son tour, la nucléation de filaments de pro-caspase-1 [4]. Ces inflammasomes forment des specks (ou structures ponctiformes) d'une taille de l'ordre du micron, visibles en microscopie, et qui sont uniques pour une cellule. NLRP3 (nucleotide-binding domain leucin-rich repeat [LRR] and pyrin-containing receptor 3, nommé également cryopyrin, CIAS1 [cold autoinflammatory syndrome 1 protein] ou NALP3 [NACHT, LRR and PYD domains-containing protein 3]) a été initialement décrit pour son association génétique avec des syndromes auto-inflammatoires héréditaires monogéniques dominants, nommés CAPS (cryopyrin-associated periodic syndrome) ou cryopyrinopathies [5]. Depuis, NLRP3 a été impliqué dans de nombreuses pathologies multifactorielles à composante inflammatoire, dont l'arthrite goutteuse, l'athérosclérose, le diabète de type 2 et la stéatose hépatique non-alcoolique [6,7]. Il est également impliqué dans plusieurs maladies neurodégénéra-tives, dont la sclérose en plaques et les maladies d'Alzheimer et de Parkinson, ainsi que dans les pathologies associées au vieillissement [6][7][8][9]. NLRP3 est aussi important au cours des infections par diffé-rents pathogènes. Il intervient en effet dans la reconnaissance de

show abstract

Pyrin Inflammasome Activation Abrogates Interleukin‐1 Receptor Antagonist, Suggesting a New Mechanism Underlying Familial Mediterranean Fever Pathogenesis

Mortensen

Hansen

Mogensen

et al. 2021

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective. Aberrant pyrin inflammasome activity triggers familial Mediterranean fever (FMF) pathogenesis, but the exact mechanism remains elusive and an obstacle to efficient treatment. We undertook this study to identify pyrin inflammasome-specific mechanisms to improve FMF treatment and diagnostics in the future.Methods. Pyrin-specific protein secretion was assessed by proteome analysis in U937-derived macrophages, and specific findings were confirmed in pyrin inflammasome-activated monocytes from healthy blood donors and patients with FMF, stratified according to MEFV genotype categories corresponding to a suspected increase in FMF disease severity.Results. Proteome data revealed a differential secretion pattern of interleukin-1 receptor antagonist (IL-1Ra) from pyrin-and NLRP3-activated U937-derived macrophages, which was verified by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Moreover, pyrin activation significantly reduced IL1RN messenger RNA expression (P < 0.001) and IL-1Ra secretion (P < 0.01) in healthy donor and FMF monocytes, respectively. Independent of MEFV genotype, unstimulated FMF monocytes from colchicine-treated patients secreted lower amounts of IL-1Ra compared to healthy donors (P < 0.05) and displayed decreased ratios of IL-1Ra:IL-1β (P < 0.05), suggesting a reduced antiinflammatory capacity.Conclusion. Our data show an inherent lack of IL-1Ra expression specific to pyrin inflammasome activation, suggesting a new mechanism underlying FMF pathogenesis. The reduced IL-1Ra levels in FMF monocytes suggest a diminished antiinflammatory capacity that potentially leaves FMF patients sensitive to proinflammatory stimuli, regardless of receiving colchicine therapy. Thus, considering the potential clinical consequence of reduced monocyte IL-1Ra secretion in FMF patients, we suggest further investigation into IL-1Ra dynamics and its potential implications for FMF treatment in the future.

show abstract

Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome

Cited by 65 publications

References 43 publications

Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients

Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients

NLRP3, un inflammasome sous contrôle

Pyrin Inflammasome Activation Abrogates Interleukin‐1 Receptor Antagonist, Suggesting a New Mechanism Underlying Familial Mediterranean Fever Pathogenesis

Contact Info

Product

Resources

About