"This is the peer reviewed version of the following article: Francos-Quijorna I, Amo-Aparicio J, Martinez-Muriana A, López-Vales R. IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair andfunctional recovery after spinal cord injury. Glia. 2016 Dec;64(12):2079-2092 ABSTRACTMacrophages and microglia play a key role in the maintenance of nervous system homeostasis.However, upon different challenges, they can adopt several phenotypes, which may lead to divergent effects on tissue repair. After spinal cord injury (SCI), microglia and macrophages show predominantly pro-inflammatory activation and contribute to tissue damage. However, the factors that hamper their conversion to an anti-inflammatory state after SCI, or to other protective phenotypes, are poorly understood. Here, we show that IL-4 protein levels are undetectable in the spinal cord after contusion injury, which likely favors microglia and macrophages to remain in a pro-inflammatory state. We also demonstrate that a single delayed intraspinal injection of IL-4, 48hours after SCI, induces increased expression of M2 marker in microglia and macrophages. We also show that delayed injection of IL-4 leads to the appearance of resolution-phase macrophages, and that IL-4 enhances resolution of inflammation after SCI. Interestingly, we provide clear evidence that delayed administration of IL-4 markedly improves functional outcomes and reduces tissue damage after contusion injury. It is possible that these improvements are mediated by the presence of macrophages with M2 markers and resolution-phase macrophages. These data suggest that therapies aimed at increasing IL-4 levels could be valuable for the treatment of acute SCI, for which there are currently no effective treatments.
Background 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. Methods 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. Results 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. Conclusions 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. Electronic supplementary material The online version of this article (10.1186/s12974-019-1511-7) contains supplementary material, which is available to authorized users.
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