BET protein inhibition regulates cytokine production and promotes neuroprotection after spinal cord injury
Sánchez-Ventura, Judith (Universitat Autònoma de Barcelona. Institut de Neurociències)
Amo Aparicio, Jesús (Universitat Autònoma de Barcelona. Institut de Neurociències)
Navarro, X. (Xavier) (Xavier) (Universitat Autònoma de Barcelona. Institut de Neurociències)
Penas Pérez, Clara (Universitat Autònoma de Barcelona. Institut de Neurociències)
Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular

Data:	2019
Resum:	Spinal cord injury (SCI) usually causes a devastating lifelong disability for patients. After a traumatic lesion, disruption of the blood-spinal cord barrier induces the infiltration of macrophages into the lesion site and the activation of resident glial cells, which release cytokines and chemokines. These events result in a persistent inflammation, which has both detrimental and beneficial effects, but eventually limits functional recovery and contributes to the appearance of neuropathic pain. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that regulate the expression of inflammatory genes by interacting with acetylated lysine residues. While BET inhibitors are a promising therapeutic strategy for cancer, little is known about their implication after SCI. Thus, the current study was aimed to investigate the anti-inflammatory role of BET inhibitors in this pathologic condition. We evaluated the effectiveness of the BET inhibitor JQ1 to modify macrophage reactivity in vitro and to modulate inflammation in a SCI mice model. We analyzed the effects of BET inhibition in pro-inflammatory and anti-inflammatory cytokine production in vitro and in vivo. We determined the effectiveness of BET inhibition in tissue sparing, inflammation, neuronal protection, and behavioral outcome after SCI. We have found that the BET inhibitor JQ1 reduced the levels of pro-inflammatory mediators and increased the expression of anti-inflammatory cytokines. A prolonged treatment with JQ1 also decreased reactivity of microglia/macrophages, enhanced neuroprotection and functional recovery, and acutely reduced neuropathic pain after SCI. BET protein inhibition is an effective treatment to regulate cytokine production and promote neuroprotection after SCI. These novel results demonstrate for the first time that targeting BET proteins is an encouraging approach for SCI repair and a potential strategy to treat other inflammatory pathologies. The online version of this article (10. 1186/s12974-019-1511-7) contains supplementary material, which is available to authorized users.
Ajuts:	Instituto de Salud Carlos III RD16/0011/0014 Instituto de Salud Carlos III CB06/05/1105
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	BET protein ; Inflammation ; Cytokine ; Neuroprotection ; Spinal cord injury
Publicat a:	Journal of neuroinflammation, Vol. 16 (June 2019) , art. 124, ISSN 1742-2094

DOI: 10.1186/s12974-019-1511-7
PMID: 31186006

12 p, 3.0 MB

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