Murine astrocytes produce IL-24 and are susceptible to the immunosuppressive effects of this cytokine
Murine astrocytes produce IL-24 and are susceptible to the immunosuppressive effects of this cytokine
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DOI：
10.1186/s12974-019-1444-1
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发表时间：
2019-03-02
影响因子：
9.3
通讯作者：
Marriott, Ian
中科院分区：
文献类型：
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作者：
Burmeister, Amanda R.;Johnson, M. Brittany;Marriott, Ian
背景Glia是感染或创伤后中枢神经系统(CNS)炎症反应的关键调节因子。我们之前已经证明了激活的胶质细胞快速产生促炎介质的能力，随后过渡到抗炎细胞因子产生谱，其中包括免疫抑制细胞因子IL-10和密切相关的细胞因子IL-19。IL-24是IL-10家族的另一个成员，已经在许多外周炎症条件下进行了研究，已知它可以调节免疫细胞的活动。然而，胶质细胞产生IL-24的能力尚不清楚，这种多效性细胞因子对胶质细胞免疫功能的影响尚未被研究。方法在本研究中，我们评估了原代小鼠神经胶质细胞在刺激后是否产生IL-24，并评价了这种细胞因子对这些细胞免疫反应的影响。我们利用RT-PCR和免疫印迹分析来评估细菌或其成分攻击后星形胶质细胞IL-24及其同源受体的表达。此外，我们还利用RT-PCR和特异性捕获ELIS检测了重组IL-24对星形胶质细胞免疫信号和对临床相关细菌反应的影响。结果我们发现，在细菌攻击后，星形胶质细胞表达IL-24 mRNA，并延迟释放可检测到的这种细胞因子蛋白。此外，我们已经确定胶质细胞结构性地表达IL-24的同源受体，并表明这种表达可以在激活后在星形胶质细胞中增加。重要的是，我们的结果表明，IL-24通过上调细胞因子信号转导抑制因子3的表达，并在攻击后限制IL-6的产生，对星形胶质细胞产生免疫抑制作用。此外，我们还证实了IL-24还可以促进细菌攻击星形胶质细胞释放IL-10，并诱导潜在的神经保护介质谷氨酸转运体1和环氧合酶2的表达。结论细菌攻击后星形胶质细胞IL-24及其同源受体的表达，以及这种细胞因子在促进免疫抑制和/或神经保护介质表达的同时限制炎症反应的能力，增加了IL-24调节或缓解细菌感染后中枢神经系统炎症以限制神经元损伤的可能性。
BackgroundGlia are key regulators of inflammatory responses within the central nervous system (CNS) following infection or trauma. We have previously demonstrated the ability of activated glia to rapidly produce pro-inflammatory mediators followed by a transition to an anti-inflammatory cytokine production profile that includes the immunosuppressive cytokine interleukin (IL)-10 and the closely related cytokine IL-19. IL-24, another member of the IL-10 family, has been studied in a number of inflammatory conditions in the periphery and is known to modulate immune cell activity. However, the ability of glia to produce IL-24 remains unclear and the effects of this pleiotropic cytokine on glial immune functions have not been investigated.MethodsIn this study, we have assessed whether primary murine glia produce IL-24 following stimulation and evaluated the effect of this cytokine on the immune responses of such cells. We have utilized RT-PCR and immunoblot analyses to assess the expression of IL-24 and its cognate receptors by astrocytes following challenge with bacteria or their components. Furthermore, we have determined the effect of recombinant IL-24 on astrocyte immune signaling and responses to clinically relevant bacteria using RT-PCR and specific capture ELISAs.ResultsWe demonstrate that astrocytes express IL-24 mRNA and release detectable amounts of this cytokine protein in a delayed manner following bacterial challenge. In addition, we have determined that glia constitutively express the cognate receptors for IL-24 and show that such expression can be increased in astrocytes following activation. Importantly, our results indicate that IL-24 exerts an immunosuppressive effect on astrocytes by elevating suppressor of cytokine signaling 3 expression and limiting IL-6 production following challenge. Furthermore, we have demonstrated that IL-24 can also augment the release of IL-10 by bacterially challenged astrocytes and can induce the expression of the potentially neuroprotective mediators, glutamate transporter 1, and cyclooxygenase 2.ConclusionsThe expression of IL-24 and its cognate receptors by astrocytes following bacterial challenge, and the ability of this cytokine to limit inflammatory responses while promoting the expression of immunosuppressive and/or neuroprotective mediators, raises the intriguing possibility that IL-24 functions to regulate or resolve CNS inflammation following bacterial infection in order to limit neuronal damage.