Publication: Relevancia fisiopatológica de la reprogramación de
mácrofagos por antifolatos
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2022-03-16
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Universidad Complutense de Madrid
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Abstract
Los macrófagos son células del sistema inmunitario innato que exhiben una gran plasticidad fenotípica y funcional. La integración de señales derivadas de su ontogenia y del microambiente donde se localizan determinan diferentes estados de polarización. Esta versatilidad funcional les permite estar implicados tanto en el inicio de procesos inflamatorios en respuesta a patógenos como en el mantenimiento de la integridad tisular y resolución de la inflamación. Así, la desregulación de macrófagos está ligada al desarrollo y perpetuación de patologías autoinmunes asociadas con la inflamación crónica como la artritis reumatoide (AR) en la que los macrófagos contribuyen significativamente a la inflamación del tejido sinovial (sinovitis) y a la destrucción articular. El mecanismo de acción del metotrexato (MTX), fármaco antinflamatorio de primera elección en el tratamiento de la AR, no está completamente elucidado y se carece de marcadores de respuesta clínica validados. El MTX actúa selectivamente en macrófagos polarizados por GM-CSF(GM-MØ) in vitro en los que establece un estado de tolerancia (memoria inmune innata) contra estímulos proinflamatorios. Para evaluar la capacidad del MTX de inducir un estado de tolerancia cruzada a LPS in vivo y determinar el tiempo-respuesta de dicho efecto se realizó el ensayo clínico EudraCT 2017-002902-11, que consistió en la administración de una dosis de MTX a seis sujetos sanos y la determinación de la concentración de citoquinas antes (basal) y después (3h, 24h y 120h)de la toma de MTX en sangre periférica, monocitos y macrófagos, y del perfil transcripcional de monocitos. En comparación con los niveles basales, la concentración de IL-6, IL-1β, IL-10 (en plasma)y TNF-α (en monocitos) en respuesta a LPS es menor 5 días después de la toma de MTX; y, losmonocitos presentan un perfil transcripcional menos proinflamatorio y más profibrótico y reparador...
Macrophages are cells of the innate immune system that exhibit a huge phenotypic and functional plasticity. The integration of signals derived from their ontogeny and the stimuli from the microenvironment determine different states of polarization. This functional versatility allows macrophages to be involved in the initiation of inflammatory response to pathogens, in tissue maintenance and repair and in the resolution of inflammation. Therefore, macrophage dysregulation is linked to the development and perpetuation of autoimmune pathologies associated with chronic inflammation such as rheumatoid arthritis (RA) in which macrophages contribute significantly to synovitis and joint destruction.The mechanism of action of methotrexate (MTX), the anchor antiinflammatory drug for RAtreatment, remains inconclusive. Importantly, no robust markers exist for MTX responsiveness. MTX acts selectively targets GM-CSF-polarized macrophages (GM-MØ) where MTX establishes a state of innate immune tolerance against proinflammatory stimuli in vitro. The aim of this study was to evaluate the capacity of MTX to induce a state of cross-tolerance to LPS (innate immune memory) in vivo and to determine the kinetic of this effect. We carried out the clinical trial EudraCT 2017-002902-11 in which six healthy volunteers received a single dose of MTX. The production of cytokines in response to LPS in whole blood, monocytes and macrophages and the transcriptional profile of monocytes were determined before (baseline) and after (3h, 24h and 120h) MTX intake. 5 days (120h) after MTX intake a significant reduction in LPS-induced IL-6, IL-1β and IL-10 (in whole blood) and TNF-α (in monocytes) was found respect to baseline levels. Moreover, monocytes exhibited aless pro-inflammatory and more profibrotic transcriptomic profile 5 days after MTX intake...
Macrophages are cells of the innate immune system that exhibit a huge phenotypic and functional plasticity. The integration of signals derived from their ontogeny and the stimuli from the microenvironment determine different states of polarization. This functional versatility allows macrophages to be involved in the initiation of inflammatory response to pathogens, in tissue maintenance and repair and in the resolution of inflammation. Therefore, macrophage dysregulation is linked to the development and perpetuation of autoimmune pathologies associated with chronic inflammation such as rheumatoid arthritis (RA) in which macrophages contribute significantly to synovitis and joint destruction.The mechanism of action of methotrexate (MTX), the anchor antiinflammatory drug for RAtreatment, remains inconclusive. Importantly, no robust markers exist for MTX responsiveness. MTX acts selectively targets GM-CSF-polarized macrophages (GM-MØ) where MTX establishes a state of innate immune tolerance against proinflammatory stimuli in vitro. The aim of this study was to evaluate the capacity of MTX to induce a state of cross-tolerance to LPS (innate immune memory) in vivo and to determine the kinetic of this effect. We carried out the clinical trial EudraCT 2017-002902-11 in which six healthy volunteers received a single dose of MTX. The production of cytokines in response to LPS in whole blood, monocytes and macrophages and the transcriptional profile of monocytes were determined before (baseline) and after (3h, 24h and 120h) MTX intake. 5 days (120h) after MTX intake a significant reduction in LPS-induced IL-6, IL-1β and IL-10 (in whole blood) and TNF-α (in monocytes) was found respect to baseline levels. Moreover, monocytes exhibited aless pro-inflammatory and more profibrotic transcriptomic profile 5 days after MTX intake...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 18-01-2022