Instituto de Inmunología, Genética y Metabolismo (INIGEM), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Center for NanoBiotechnology Research and Department of Biological Sciences, Alabama State University, Montgomery, AL, United States.
Front Immunol. 2024 Jan 23;14:1343503. doi: 10.3389/fimmu.2023.1343503. eCollection 2023.
Inflammation plays a key role in the pathogenesis of neurobrucellosis where glial cell interactions are at the root of this pathological condition. In this study, we present evidence indicating that soluble factors secreted by -infected astrocytes activate microglia to induce neuronal death. Culture supernatants (SN) from -infected astrocytes induce the release of pro-inflammatory mediators and the increase of the microglial phagocytic capacity, which are two key features in the execution of live neurons by primary phagocytosis, a recently described mechanism whereby -activated microglia kills neurons by phagocytosing them. IL-6 neutralization completely abrogates neuronal loss. IL-6 is solely involved in increasing the phagocytic capacity of activated microglia as induced by SN from -infected astrocytes and does not participate in their inflammatory activation. Both autocrine microglia-derived and paracrine astrocyte-secreted IL-6 endow microglial cells with up-regulated phagocytic capacity that allows them to phagocytose neurons. Blocking of IL-6 signaling by soluble gp130 abrogates microglial phagocytosis and concomitant neuronal death, indicating that IL-6 activates microglia via trans-signaling. Altogether, these results demonstrate that soluble factors secreted by -infected astrocytes activate microglia to induce, via IL-6 trans-signaling, the death of neurons. IL-6 signaling inhibition may thus be considered a strategy to control inflammation and CNS damage in neurobrucellosis.
炎症在神经布鲁氏菌病的发病机制中起着关键作用，其中神经胶质细胞的相互作用是这种病理状况的根源。在这项研究中，我们提供了证据表明，感染的星形胶质细胞分泌的可溶性因子激活小胶质细胞，诱导神经元死亡。感染的星形胶质细胞的培养上清液（SN）诱导促炎介质的释放和小胶质细胞吞噬能力的增加，这是通过原发性吞噬作用执行活神经元的两个关键特征，这是一种最近描述的机制，即激活的小胶质细胞通过吞噬神经元而杀死神经元。IL-6 中和完全阻断神经元丢失。IL-6 仅参与由感染的星形胶质细胞 SN 诱导的激活小胶质细胞吞噬能力的增加，而不参与其炎症激活。源自自分泌小胶质细胞和旁分泌星形胶质细胞的 IL-6 赋予小胶质细胞上调的吞噬能力，使其能够吞噬神经元。可溶性 gp130 阻断 IL-6 信号转导可阻断小胶质细胞吞噬作用和伴随的神经元死亡，表明 IL-6 通过跨信号转导激活小胶质细胞。总之，这些结果表明，感染的星形胶质细胞分泌的可溶性因子激活小胶质细胞，通过 IL-6 跨信号转导诱导神经元死亡。因此，抑制 IL-6 信号转导可能被认为是控制神经布鲁氏菌病中的炎症和中枢神经系统损伤的一种策略。
