Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Neurobiol Dis. 2010 Dec;40(3):663-75. doi: 10.1016/j.nbd.2010.08.010. Epub 2010 Aug 19.
Microglia constitute the brain's immunocompetent cells and are intricately implicated in numerous inflammatory processes included in neonatal brain injury. In addition, clearance of tissue debris by microglia is essential for tissue homeostasis and may have a neuroprotective outcome. Since unconjugated bilirubin (UCB) has been proven to induce astroglial immunological activation and neuronal cell death, we addressed the question of whether microglia acquires a reactive phenotype when challenged by UCB and intended to characterize this response. In the present study we report that microglia primary cultures stimulated by UCB react by the acquisition of a phagocytic phenotype that shifted into an inflammatory response characterized by the secretion of the pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, upregulation of cyclooxygenase (COX)-2 and increased matrix metalloproteinase (MMP)-2 and -9 activities. Further investigation upon upstream signalling pathways revealed that UCB led to the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB at an early time point, suggesting that these pathways might underlie both the phagocytic and the inflammatory phenotypes engaged by microglia. Curiously, the phagocytic and inflammatory phenotypes in UCB-activated microglia seem to alternate along time, indicating that microglia reacts towards UCB insult firstly with a phagocytic response, in an attempt to constrain the lesion extent and comprising a neuroprotective measure. Upon prolonged UCB exposure periods, either a shift on global microglia reaction occurred or there could be two distinct sub-populations of microglial cells, one directed at eliminating the damaged cells by phagocytosis, and another that engaged a more delayed inflammatory response. In conclusion, microglial cells are relevant partners to consider during bilirubin encephalopathy and the modulation of its activation might be a promising therapeutic target.
小胶质细胞构成了大脑的免疫活性细胞，并且在包括新生儿脑损伤在内的许多炎症过程中都有密切的牵连。此外，小胶质细胞清除组织碎片对于组织内稳态至关重要，并且可能具有神经保护作用。由于未结合胆红素 (UCB) 已被证明可诱导星形胶质细胞免疫激活和神经元细胞死亡，因此我们提出了一个问题，即 UCB 刺激的小胶质细胞是否会获得反应性表型，并旨在描述这种反应。在本研究中，我们报告说，UCB 刺激的小胶质细胞原代培养物通过获得吞噬表型来反应，这种反应转变为以促炎细胞因子肿瘤坏死因子 (TNF)-α、白细胞介素 (IL)-1β 和 IL-6 的分泌为特征的炎症反应，环氧合酶 (COX)-2 的上调和基质金属蛋白酶 (MMP)-2 和 -9 活性的增加。对上游信号通路的进一步研究表明，UCB 在早期导致丝裂原活化蛋白激酶 (MAPKs) 和核因子 (NF)-κB 的激活，表明这些途径可能是小胶质细胞参与的吞噬和炎症表型的基础。奇怪的是，UCB 激活的小胶质细胞中的吞噬和炎症表型似乎随着时间的推移而交替出现，表明小胶质细胞首先对 UCB 损伤做出吞噬反应，试图限制病变程度并包含神经保护措施。在延长的 UCB 暴露期后，要么小胶质细胞的整体反应发生转变，要么可能存在两种不同的小胶质细胞亚群，一种通过吞噬作用来消除受损细胞，另一种则发生更延迟的炎症反应。总之，小胶质细胞是胆红素脑病期间需要考虑的重要伙伴，其激活的调节可能是一个有前途的治疗靶点。
