Proceedings of the 24th Paediatric Rheumatology European Society Congress: Part one
Notice bibliographique
Résumé
Introduction: Juvenile-onset Systemic Lupus Erythematosus (JSLE) is a severe autoimmune disease causing organ damage and long-term morbidity.Impaired clearance of nuclear debris from cells and upregulated circulating damage-associated molecular patterns (DAMPs) and cytokines are thought to trigger cell death and thus, further increase release of pro-inflammatory molecules following the cytosolic assembly of inflammasomes.Objectives: To investigate the role of pyroptotic cell death in JSLE, which occurs following the assembly and activation of the NLRP3 inflammasome, which may be a promising target in the treatment of JSLE and other inflammatory diseases.Methods: THP-1 cell line-derived macrophages (Mφs) were primed using lipopolysaccharide (LPS; 10 ng/ml) and interferon (IFN) γ (20 ng/ml) in complete media at 37 °C for 24 hours, and subsequently treated with 10 mM Adenosine triphosphate (ATP) for 30 min.Primed Mφs not treated with ATP were used as a negative control.Some Mφs were incubated with 10% JSLE patient sera or NETosis-derived material (10 ng/ml) from PMA-treated neutrophils.Primed Mφs were tested for cell surface markers, HLA-DR, CD282 (TLR2), and CD68 using flow cytometry.ATP-treated Mφs were collected and either assayed for pyroptosis marker, lactate dehydrogenase (LDH) activity, cleaved caspase-1 with immunofluorescence (IF), or lysed for cleaved caspase-1 using western blotting.Results: Primed Mφs showed an M1 phenotype with geometric means ± SEM of HLA-DR, TLR2 and CD68 expression respectively of: 1177 ± 1.15, 613 ± 0.9, and 1549 ± 0.9 gMFI, respectively compared with un-primed Mφs of 597 ± 1.0, 122 ± 0.88, and 1225 ± 0.9 gMFI, respectively (n = 3; p < 0.05).ATP-treated Mφs showed increased LDH activity compared to controls (3.4x10 -3 ± 0.12x10 -3 ) compared to 0.00 milliunits/ mL, respectively; n = 3; p < 0.05).Furthermore, a greater increase in LDH activity was observed in Mφs that were incubated with JSLE serum and NET material (3.7x10 -3 ± 0.5x10 -3 and 7.6x10 -3 ± 0.5x10 -3 , respectively, compared to 0.00 milliunits/mL; n = 3-6; p < 0.05).IF was positive for cleaved caspase-1 in ATP treated Mφs; and this was confirmed in lysed cells, using western blotting. Conclusion:Overall, the results indicate that Mφs undergo pyroptosis via the NLRP3 inflammasome when challenged with a two-signal approach of priming and ATP, and that cytokines, nuclear debris and DAMPs may not only trigger, but amplify the inflammatory response of this pathway.The NLRP3 inflammasome is thought to be an important mediator in the pathogenesis of certain inflammatory diseases, and flare episodes associated with JSLE.Further work is planned to investigate the role of the inflammasome in JSLE, using pharmacological interventions with specific known and novel inhibitors of the NLRP3 inflammasome.This work could prove the NLRP3 inflammasome to be a promising target for future therapy for JSLE.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».