A type 1 immunity-restricted promoter of the IL-33 receptor gene directs antiviral T-cell responses.

The pleiotropic alarmin interleukin-33 (IL-33) drives type 1, type 2 and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33-ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type 1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type 1- but not type 2-biased T cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper 1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type 1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33-ST2 axis in infections and inflammatory diseases.

NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis.

Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 (NOS2) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2-/- mice were protected from age-related OA development. Taken together, the TLR2-NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.

[The DRFZ-a pioneer in research on the interaction between immune and stromal cells during de- and regeneration of the musculoskeletal system]. / Das DRFZ ­ ein Vorreiter bei der Erforschung des Zusammenspiels von Immun- und Stromazellen bei der De- und Regeneration des Bewegungsapparats.

Rheumatoid arthritis and osteoarthritis are two related chronic diseases of the musculoskeletal system which are particularly pronounced in the region of joints and bones. Their pathogeneses are associated with chronic inflammation, which can disrupt homeostasis in bones and articular cartilage. Degradation products deriving from articular cartilage can contribute to the exacerbation of inflammation in the joint region. Mechanical stimuli and blood vessels also play a central role in both the regulation of bone growth as well as in the regeneration of bone tissue. Not only chronic inflammatory processes but also hormonal changes after menopause or undesired effects of glucocorticoid therapy have an influence on the balance between bone resorption and deposition, by promoting the former and reducing the latter. This results in decreased bone quality and, in some cases, considerable loss of bone or osteoporosis. An in-depth understanding of these processes at the molecular, cellular, and tissue level, as well as of the changes present in chronic inflammatory diseases, has been the focus of research at the German Rheumatism Research Center (Deutsches Rheuma-Forschungszentrum, DRFZ) since its foundation. Based on an improved understanding of these mechanisms, the DRFZ aims to develop improved prevention and treatment strategies with effects even in early disease stages.

Osteoarthritis of the hip conservative treatment with type A botulinum toxin.

INTRODUCTION: Osteoarthritis (OA) of the hip is a low-grade inflammatory disease of multiple etiology that has a limited conservative management and insufficiently explored. The application of botulinum toxin type A (BoNT-A) produces in the applied muscle a temporary, delimitable and reversible flaccid paralysis, which applied in a strategic way achieves to reduce mechanical stress and pain. OBJECTIVE: To evaluate the effect on pain perception, functionality and rigidity and changes in flexibility, internal and external rotation, before and 90 days after the application of BoNT-A. METHODS: Clinical, experimental, longitudinal, open study, with a total of 35 patients and 45 hips treated. BoNT-A of 500 U was applied in iliac, adductor brevis and longus muscles. RESULTS: The Wilcoxon test was used to compare the evaluation scores on days 0-90, observing the decrease in referred pain (p < 0.0001), rigidity (p < 0.002), improved perceived function (p < 0.001) and mobility arcs: flexion, internal and external rotation (p < 0.0001). CONCLUSIONS: The treatment with BoNT-A provides a conservative and safe option for the management of symptoms and physical restraint caused by hip OA.

[Tratamiento conservador de la osteoartrosis de cadera con toxina botulínica tipo A].

INTRODUCTION: Osteoarthritis (OA) of the hip is a low-grade inflammatory disease of multiple etiology that has a limited conservative management and insufficiently explored. The application of botulinum toxin type A (BoNT-A) produces in the applied muscle a temporary, delimitable and reversible flaccid paralysis, which applicated in a strategic way achives to reduce mechanical stress and pain. OBJECTIVE: To evaluate the effect on pain perception, functionality and rigidity and changes in flexibility, internal and external rotation, before and 90 days after the application of BoNT-A. METHODS: Clinical, experimental, longitudinal, open study, with a total of 35 patients and 45 hips treated. BoNT-A of 500 U was applied in iliac, adductor brevis and longus muscles. RESULTS: The Wilcoxon test was used to compare the evaluation scores on days 0-90, observing the decrease in referred pain (p < 0.0001), rigidity (p < 0.002), improved perceived function (p < 0.001) and mobility arcs: flexion, internal and external rotation (p < 0.0001). CONCLUSIONS: The treatment with BoNT-A provides a conservative and safe option for the management of symptoms and physical restraint caused by hip OA.

INTRODUCCIÓN: La osteoartritis de cadera es una enfermedad articular inflamatoria de bajo grado y etiología múltiple que tiene un manejo conservador limitado y poco explorado. La aplicación de toxina botulínica tipo A (BoNT-A) produce en el músculo aplicado una parálisis flácida temporal, delimitable y reversible, que aplicada de manera estratégica logra liberar estrés mecánico y dolor. OBJETIVO: Evaluar el efecto en la percepción de dolor, funcionalidad y rigidez y los cambios en la flexión, rotación interna y externa, antes y 90 días después de la aplicación de BoNT-A. MÉTODOS: Estudio clínico, experimental, longitudinal, abierto, con un total de 35 pacientes y 45 caderas tratadas. Se aplicó BoNT-A de 500 U en músculos ilíaco, músculo aductorbrevis y longus. RESULTADOS: Se utilizó la prueba de Wilcoxon comparando los puntajes de evaluación en los días 0 a 90 observando disminución significativa del dolor referido (p < 0.0001), rigidez (p < 0.002), mejoró la función percibida (p < 0.001) y los arcos de movilidad: flexión, rotación interna y externa (p < 0.0001). CONCLUSIONES: El tratamiento con BoNT-A otorga una opción conservadora y segura para el manejo de los síntomas y restricción física causada por la OA de cadera.

Tratamiento conservador de la osteoartrosis de cadera con toxina botulínica tipo A / Conservative treatment of hip osteoarthritis with botulinum toxin type A

Resumen Introducción: La osteoartritis de cadera es una enfermedad articular inflamatoria de bajo grado y etiología múltiple que tiene un manejo conservador limitado y poco explorado. La aplicación de toxina botulínica tipo A (BoNT-A) produce en el músculo aplicado una parálisis flácida temporal, delimitable y reversible, que aplicada de manera estratégica logra liberar estrés mecánico y dolor Objetivo: Evaluar el efecto en la percepción de dolor, funcionalidad y rigidez y los cambios en la flexión, rotación interna y externa, antes y 90 días después de la aplicación de BoNT-A. Métodos: Estudio clínico, experimental, longitudinal, abierto, con un total de 35 pacientes y 45 caderas tratadas. Se aplicó BoNT-A de 500 U en músculos ilíaco, músculo aductorbrevis y longus. Resultados: Se utilizó la prueba de Wilcoxon comparando los puntajes de evaluación en los días 0 a 90 observando disminución significativa del dolor referido (p < 0.0001), rigidez (p < 0.002), mejoró la función percibida (p < 0.001) y los arcos de movilidad: flexión, rotación interna y externa (p < 0.0001). Conclusiones: El tratamiento con BoNT-A otorga una opción conservadora y segura para el manejo de los síntomas y restricción física causada por la OA de cadera.

Abstract Introduction: Osteoarthritis (OA) of the hip is a low-grade inflammatory disease of multiple etiology that has a limited conservative management and insufficiently explored. The application of botulinum toxin type A (BoNT-A) produces in the applied muscle a temporary, delimitable and reversible flaccid paralysis, which applicated in a strategic way achives to reduce mechanical stress and pain. Objective: To evaluate the effect on pain perception, functionality and rigidity and changes in flexibility, internal and external rotation, before and 90 days after the application of BoNT-A. Methods: Clinical, experimental, longitudinal, open study, with a total of 35 patients and 45 hips treated. BoNT-A of 500 U was applied in iliac, adductor brevis and longus muscles. Results: The Wilcoxon test was used to compare the evaluation scores on days 0-90, observing the decrease in referred pain (p < 0.0001), rigidity (p < 0.002), improved perceived function (p < 0.001) and mobility arcs: flexion, internal and external rotation (p < 0.0001). Conclusions: The treatment with BoNT-A provides a conservative and safe option for the management of symptoms and physical restraint caused by hip OA.