Histamine modulates microglia function.
Histamine modulates microglia function.
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DOI：
10.1186/1742-2094-9-90
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发表时间：
2012-05-08
影响因子：
9.3
通讯作者：
Bernardino L
中科院分区：
文献类型：
--
作者：
Ferreira R;Santos T;Gonçalves J;Baltazar G;Ferreira L;Agasse F;Bernardino L
组胺通常被认为是外周组织中的一种炎症介质，对其在大脑免疫反应中的作用几乎没有研究。因此，我们的目的是通过评估细胞迁移和炎症介质的释放，揭示该分子及其受体在小胶质细胞诱导的炎症中所引发的细胞和分子机制。首先，我们利用小鼠小胶质细胞系和原代培养的大鼠大脑皮质小胶质细胞，通过实时定量聚合酶链式反应、免疫细胞化学和Western blotting检测了所有已知的组胺受体亚型(H1R、H2R、H3R和H4R)的表达。然后，我们通过划痕实验评估了组胺在小胶质细胞运动中的作用。使用小鼠皮质外植体进一步证实了这一结果。最后，用酶联免疫吸附试验检测IL-1β(IL-1β)和肿瘤坏死因子-α(TN-α)的水平，以确定组胺对这些炎症介质释放的作用。处理12h后，100μM组胺和10μg/ml组胺负载的聚乳酸-乙醇酸微球通过H4R激活显著刺激小胶质细胞的运动。此外，迁移还涉及α5和β1整合素，以及p38和Akt信号通路。作为阳性对照的脂多糖(LPS，100 ng/ml)也能促进小胶质细胞的迁移。重要的是，组胺通过激活H4R抑制了内毒素刺激的迁移。组胺或H4R激动剂也能抑制脂多糖诱导的N9小胶质细胞株和海马器型脑片中IL-1β的释放。据我们所知，我们是第一个显示组胺在调节小胶质细胞炎症反应中的双重作用的人。总之，我们的数据表明，组胺本身触发了小胶质细胞的运动，而组胺阻碍了内毒素诱导的小胶质细胞迁移和IL-1β的释放。这最后一项数据为组胺指定了一个新的假定的抗炎作用，通过H4R作用于抑制炎症刺激下加剧的小胶质细胞反应，这可能在治疗伴有小胶质细胞来源的炎症的中枢神经系统疾病方面产生强烈的影响。
Histamine is commonly acknowledged as an inflammatory mediator in peripheral tissues, leaving its role in brain immune responses scarcely studied. Therefore, our aim was to uncover the cellular and molecular mechanisms elicited by this molecule and its receptors in microglia-induced inflammation by evaluating cell migration and inflammatory mediator release. Firstly, we detected the expression of all known histamine receptor subtypes (H1R, H2R, H3R and H4R), using a murine microglial cell line and primary microglia cell cultures from rat cortex, by real-time PCR analysis, immunocytochemistry and Western blotting. Then, we evaluated the role of histamine in microglial cell motility by performing scratch wound assays. Results were further confirmed using murine cortex explants. Finally, interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels were evaluated by ELISA measurements to determine the role of histamine on the release of these inflammatory mediators. After 12 h of treatment, 100 μM histamine and 10 μg/ml histamine-loaded poly (lactic-co-glycolic acid) microparticles significantly stimulated microglia motility via H4R activation. In addition, migration involves α5β1 integrins, and p38 and Akt signaling pathways. Migration of microglial cells was also enhanced in the presence of lipopolysaccharide (LPS, 100 ng/ml), used as a positive control. Importantly, histamine inhibited LPS-stimulated migration via H4R activation. Histamine or H4R agonist also inhibited LPS-induced IL-1β release in both N9 microglia cell line and hippocampal organotypic slice cultures. To our knowledge, we are the first to show a dual role of histamine in the modulation of microglial inflammatory responses. Altogether, our data suggest that histamine per se triggers microglia motility, whereas histamine impedes LPS-induced microglia migration and IL-1β release. This last datum assigns a new putative anti-inflammatory role for histamine, acting via H4R to restrain exacerbated microglial responses under inflammatory challenge, which could have strong repercussions in the treatment of CNS disorders accompanied by microglia-derived inflammation.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1016/j.bbrc.2010.03.072
发表时间：
2010-04-09
影响因子：
3.1
作者：
Furundzija, Vesna;Fritzsche, Jan;Stawowy, Philipp
通讯作者：
Stawowy, Philipp
影响因子：
9.3
作者：
Ferreira R;Santos T;Viegas M;Cortes L;Bernardino L;Vieira OV;Malva JO
通讯作者：
Malva JO
影响因子：
4.7
作者：
Ferreira, Raquel;Santos, Tiago;Malva, Joao O.
通讯作者：
Malva, Joao O.
影响因子：
4.8
作者：
Jin, Young-June;ParkA, Iha;Lee, Hansoo
通讯作者：
Lee, Hansoo