First Report of Circulating MicroRNAs in Tumour Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder characterized by recurrent episodes of long-lasting fever and inflammation in different regions of the body, such as the musculo-skeletal system, skin, gastrointestinal tract, serosal membranes and eye. Our aims were to evaluate circulating microRNAs (miRNAs) levels in patients with TRAPS, in comparison to controls without inflammatory diseases, and to correlate their levels with parameters of disease activity and/or disease severity. Expression levels of circulating miRNAs were measured by Agilent microarrays in 29 serum samples from 15 TRAPS patients carrying mutations known to be associated with high disease penetrance and from 8 controls without inflammatory diseases. Differentially expressed and clinically relevant miRNAs were detected using GeneSpring GX software. We identified a 6 miRNAs signature able to discriminate TRAPS from controls. Moreover, 4 miRNAs were differentially expressed between patients treated with the interleukin (IL)-1 receptor antagonist, anakinra, and untreated patients. Of these, miR-92a-3p and miR-150-3p expression was found to be significantly reduced in untreated patients, while their expression levels were similar to controls in samples obtained during anakinra treatment. MiR-92b levels were inversely correlated with the number of fever attacks/year during the 1st year from the index attack of TRAPS, while miR-377-5p levels were positively correlated with serum amyloid A (SAA) circulating levels. Our data suggest that serum miRNA levels show a baseline pattern in TRAPS, and may serve as potential markers of response to therapeutic intervention

Role of granulocytes activation in the pathogenesis of Systemic juvenile idiopathic arthritis and Adult onset Still’s disease

The autoinflammatory syndromes are a group of disorders defined as “unmotivated recurrent inflammatory events” haracterized by an apparently spontaneous manifestations of inflammation, without autoreactive T cells or auto-antibody involvement. These conditions usually present aberrant responses associated to molecular pathogenic patterns and deregulated production of inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-18 (IL-18) and Tumor Necrosis Factor-α (TNF- α). Systemic juvenile idiopathic arthritis (sJIA) and Adult onset Still’s disease (AOSD) are particular kinds of autoinflammatory disorders with still unknown etiology, mainly associated to the possible pathogenic role of IL-1β, since the efficiency of pharmacological treatments with IL-1β blockers agents. The typical patients’ neutrophilia would presume the PMNs involvement at the onset of these syndromes. For this reason we have analyzed the PMNs activation state at baseline, together with their response to extracellular pro-inflammatory stimuli. In comparison with healthy granulocytes, sJIA and AOSD PMNs didn’t present differences in term of cellular activation state and IL-1β production, and our results also revealed that neither healthy nor sJIA/AOSD PMNs can produce elevated levels of this cytokine, as opposed to monocytes, which can release IL-concentrations more than 10 fold higher than PMNs. We have also analyzed the inflammatory response mediated by monocytes, after activation of three different inflammasome complexes, in sJIA, AOSD patients and patients affected by the hereditary periodic fever syndromes (HPFs) Familial Mediterranean Fever (FMF) and Cryopyrin associated periodic syndrome (CAPS). Monocytes from HPFs affected patients have shown the clear involvement of one specific inflammasome complex. sJIA and AOSD monocytes, instead, have not presented significant differences with healthy monocytes, leaving some doubts about the principal cellular source of IL-1β in these syndromes, also considering previous experiments which indicated that sJIA monocytes released even lower IL-1β concentrations than healthy monocytes. An important difference has been observed about the S100 calcium-binding protein A12 (S100A12) production. Indeed, patients PMNs have produced higher levels of S100A12 after stimulation in comparison with healthy ones. This result could be related to the typical elevated S100A12 serum concentration observed in affected patients. Taken together, our observations indicate that the role of PMNs in sJIA and AOSD is not directly related to the inflammasome activity and IL-1β production, but it deserves further investigations about a possible different action mechanism, involved in the pathogenesis of these syndromes

Functional Assessment of Disease-Associated Pyrin Variants

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The pyrin inflammasome: from sensing RhoA GTPases-inhibiting toxins to triggering autoinflammatory syndromes

International audienceNumerous pathogens including Clostridium difficile and Yersinia pestis have evolved toxins or effectors targeting GTPases from the RhoA subfamily (RhoA/B/C) to inhibit or hijack the host cytoskeleton dynamics. The resulting impairment of RhoA GTPases activity is sensed by the host via an innate immune complex termed the pyrin inflammasome in which caspase-1 is activated. The cascade leading to activation of the pyrin inflammasome has been recently uncovered. In this review, following a brief presentation of RhoA GTPases-modulating toxins, we present the pyrin inflammasome and its regulatory mechanisms. Furthermore, we discuss how some pathogens have developed strategies to escape detection by the pyrin inflammasome. Finally, we present five monogenic autoinflammatory diseases associated with pyrin inflammasome deregulation. The molecular insights provided by the study of these diseases and the corresponding mutations on pyrin inflammasome regulation and activation are presented

Weekly oral alendronate in mevalonate kinase deficiency

BACKGROUND: Mevalonate kinase deficiency (MKD) is caused by mutations in the MVK gene, encoding the second enzyme of mevalonate pathway, which results in subsequent shortage of downstream compounds, and starts in childhood with febrile attacks, skin, joint, and gastrointestinal symptoms, sometimes induced by vaccinations. METHODS: For a history of early-onset corticosteroid-induced reduction of bone mineral density in a 14-year-old boy with MKD, who also had presented three bone fractures, we administered weekly oral alendronate, a drug widely used in the management of osteoporosis and other high bone turnover diseases, which blocks mevalonate and halts the prenylation process. RESULTS: All of the patient's MKD clinical and laboratory abnormalities were resolved after starting alendronate treatment. CONCLUSIONS: This observation appears enigmatic, since alendronate should reinforce the metabolic block characterizing MKD, but is crucial because of the ultimate improvement shown by this patient. The anti-inflammatory properties of bisphosphonates are a new question for debate among physicians across various specialties, and requires further biochemical and clinical investigation

Role of polymorphonucleates in the pathogenesis of systemic juvenile idiopathic arthritis and Still's disease: A proof of concept study

Role of polymorphonucleates in the pathogenesis of systemic juvenile idiopathic arthritis and Still's disease: A proof of concept stud

Geoepidemiology and Immunologic Features of Autoinflammatory Diseases: a Comprehensive Review

International audienceThe knowledge on systemic autoinflammatory disorders (SAID) is expanding rapidly and new signalling pathways are being decrypted. The concept of autoinflammation has been proposed since 1999, to define a group of diseases with abnormal innate immunity activation. Since then, more than 30 monogenic SAID have been described. In this review, we first describe inflammasomopathies and SAID related to the interleukin-1 pathway. Recent insights into the pathogenesis of familial Mediterranean fever and the function of Pyrin are detailed. In addition, complex or polygenic SAID, such as Still’s disease or PFAPA syndrome, are also discussed. Then, major players driving autoinflammation, such as type-1 interferonopathies (including the recently described haploinsuffiency in A20 and otulipenia), TNF-associated periodic syndromes, defects in ubiquitination, and SAID with overlapping features of autoimmunity or immunodeficiency. Discoveries of the pathogenic role of mosaicism, intronic defects coupled to the likelihood to identify digenic or polygenic diseases are providing new challenges for physicians and geneticists. This comprehensive review depicts the various SAID, presenting them according to their predominant pathophysiological mechanism, with a particular emphasis on recent findings. Epidemiologic data are also presented. Finally, we propose a practical diagnostic approach to the most common monogenic SAID, based on the most characteristic clinical presentation of these disorders

Phosphoprotein phosphatase activity positively regulates oligomeric pyrin to trigger inflammasome assembly in phagocytes

ABSTRACT Pyrin is a pattern-recognition receptor in phagocytes that triggers caspase-1 inflammasome assembly in response to bacterial toxins and effectors that inactivate RhoA. Pyrin contains oligomerization domains and is negatively regulated by phosphorylation of two residues, S205 and S241 (murine) or S208 and S242 (human), via the kinases PKN1/2, which are activated by RhoA. Familial Mediterranean Fever (FMF) is caused by the phagocyte production of pyrin gain of function variants, which have a lower threshold for inflammasome assembly upon RhoA-PKN axis inhibition. Inactivation of the RhoA-PKN axis removes negative regulation but a phosphoprotein phosphatase (PPP) is needed to positively regulate pyrin. No PPP that dephosphorylates pyrin has been identified, oligomerization of murine pyrin has not been studied, and the phosphorylation status of oligomeric pyrin is unknown. We used murine macrophages and FMF patient’s monocytes combined with the use of bacterial agonists and chemical inhibitors, native PAGE, phospho-specific antibodies, and siRNA knockdowns to determine if a PPP positively regulates oligomeric pyrin. Results with broadly specific inhibitors indicate that PPP activity is required to dephosphorylate murine and human pyrin in wild-type or FMF patient’s phagocytes. Findings from native PAGE show that murine pyrin is oligomeric and phosphorylated on S205 prior to RhoA inactivation. PPP inhibitors cause reduced mobility of murine pyrin on native PAGE and increased phosphorylation of S242 in human pyrin, suggesting a PPP constitutively counterbalances PKN to regulate second-site phosphorylation. Data from siRNA knockdown experiments implicate PP2A in dephosphorylation of S205 and positive regulation of pyrin in response to RhoA inactivation. IMPORTANCE Pyrin, a unique cytosolic receptor, initiates inflammatory responses against RhoA-inactivating bacterial toxins and effectors like Yersinia’s YopE and YopT. Understanding pyrin regulation is crucial due to its association with dysregulated inflammatory responses, including Familial Mediterranean Fever (FMF), linked to pyrin gene mutations. FMF mutations historically acted as a defense mechanism against plague. Negative regulation of pyrin through PKN phosphorylation is well established, with Yersinia using the YopM effector to promote pyrin phosphorylation and counteract its activity. This study highlights the importance of phosphoprotein phosphatase activity in positively regulating pyrin inflammasome assembly in phagocytic cells of humans and mice. Oligomeric murine pyrin has S205 phosphorylated before inflammasome assembly, and this study implicates the dephosphorylation of murine pyrin S205 by two catalytic subunits of PP2A in macrophages. These findings offer insights for investigating the regulation of oligomeric pyrin and the balance of kinase and phosphatase activity in pyrin-associated infectious and autoinflammatory diseases

The inflammasome adaptor ASC delays UV-induced skin tumorigenesis in Beta HPV38 E6 and E7 Transgenic mice.

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Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11

Lipid A from some bacteria is sensed differently by humans and mice for the activation of the inflammasomes and inflammatory responses, but the mechanisms are not clear. Here, the authors show that murine caspase-11 and human caspase-4/5 contribute to this differential response via their distinct recognition of under-acylated lipid A