RESUMO
All-trans retinoic acid (ATRA) is a derivative of vitamin A that has many important biological functions, including the modulation of immune responses. ATRA actions are mediated through the retinoic acid receptor that functions as a nuclear receptor, either regulating gene transcription in the nucleus or modulating signal transduction in the cytoplasm. NLRP3 inflammasome is a multiprotein complex that is activated by a huge variety of stimuli, including pathogen- or danger-related molecules. Activation of the inflammasome is required for the production of IL-1ß, which drives the inflammatory responses of infectious or non-infectious sterile inflammation. Here, we showed that ATRA prolongs the expression of IL-6 and IL-1ß following a 2-, 6-, 12-, and 24-h LPS (100ng/mL) activation in human monocyte-derived macrophages. We describe for the first time that ATRA modulates both priming and activation signals required for NLRP3 inflammasome function. ATRA alone induces NLRP3 expression, and enhances LPS-induced expression of NLRP3 and pro-IL-1ß via the regulation of signal transduction pathways, like NF-κB, p38, and ERK. We show that ATRA alleviates the negative feedback loop effect of IL-10 anti-inflammatory cytokine on NLRP3 inflammasome function by inhibiting the Akt-mTOR-STAT3 signaling axis. We also provide evidence that ATRA enhances hexokinase 2 expression, and shifts the metabolism of LPS-activated macrophages toward glycolysis, leading to the activation of NLRP3 inflammasome.
Assuntos
Glicólise/efeitos dos fármacos , Inflamassomos/imunologia , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Hexoquinase/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/imunologia , NF-kappa B/sangue , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tretinoína/metabolismoRESUMO
The NLRP3 inflammasome is implicated in the processing of the pro-inflammatory cytokine interleukin 1ß. Inflammatory disorders associated with the activation of the NLRP3 inflammasome - IL-1 axis are termed autoinflammatory diseases. Gout is an autoinflammatory disease, which is triggered by the deposition of monosodium urate crystals of precipitated uric acid. It is characterized by recurrent attacks of inflammation due to the activation of phagocytic cells that try to clear the crystals. NLRP3 inflammasome-mediated IL-1ß production plays a key role in the manifestation of the disease. Currently, the best approach to treat gout is to reduce uric acid concentration by targeting xanthine oxidase or uric acid transporters, or to use non-steroidal anti-inflammatory drugs. Nevertheless, most of these treatments are not effective enough and may results in side effects. During the past decades, our knowledge has greatly improved about the molecular mechanisms of NLRP3 activation. This knowledge enables and urges scientists to discover or design drugs that target pathways of NLRP3 inflammasome activation, or more preferentially, NLRP3 inflammasome itself. In this review, we discuss the already available drugs and products, that target the diverse pathways of the NLRP3 - IL-1ß axis, and the future therapeutic perspectives.