Tenascin C regulates multiple microglial functions involving TLR4 signaling and HDAC1
Tenascin C regulates multiple microglial functions involving TLR4 signaling and HDAC1
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DOI：
10.1016/j.bbi.2019.06.047
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发表时间：
2019-10-01
影响因子：
15.1
通讯作者：
Kettenmann, Helmut
中科院分区：
文献类型：
--
作者：
Haage, Verena;Elmadany, Nirmeen;Kettenmann, Helmut
腱生蛋白C（Tnc）是一种细胞外基质糖蛋白，在发育期间以及在炎症、纤维化和癌症的情况下在CNS中表达，其作为Toll样受体4（TLR 4）的激活剂起作用。尽管TLR 4在小胶质细胞中高度表达，但迄今为止尚未阐明Tnc对小胶质细胞的作用。在此，我们表明，Tnc调节小胶质细胞的吞噬活性在出生后的早期年龄（P4），这一过程是部分依赖于小胶质细胞TLR 4的表达。我们进一步表明，Tnc调节促炎细胞因子/趋化因子的生产，趋化性和吞噬作用在初级小胶质细胞中的TLR 4依赖的方式。此外，Tnc诱导小胶质细胞中的组蛋白脱乙酰酶1（HDAC 1）表达，使得MS-275对HDAC 1的抑制降低了Tnc诱导的小胶质细胞IL-6和TNF-α的产生。最后，Tnc（-/-）皮质小胶质细胞在P4时具有降低的HDAC 1表达水平。总之，这些发现建立Tnc作为小胶质细胞功能的调节剂在出生后早期的发展。
Tenascin C (Tnc) is an extracellular matrix glycoprotein, expressed in the CNS during development, as well as in the setting of inflammation, fibrosis and cancer, which operates as an activator of Toll-like receptor 4 (TLR4). Although TLR4 is highly expressed in microglia, the effect of Tnc on microglia has not been elucidated to date. Herein, we demonstrate that Tnc regulates microglial phagocytic activity at an early postnatal age (P4), and that this process is partially dependent on microglial TLR4 expression. We further show that Tnc regulates proinflammatory cytokine/chemokine production, chemotaxis and phagocytosis in primary microglia in a TLR4-dependent fashion. Moreover, Tnc induces histone-deacetylase 1 (HDAC1) expression in microglia, such that HDAC1 inhibition by MS-275 decreases Tnc-induced microglial IL-6 and TNF-alpha production. Finally, Tnc(-/-) cortical microglia have reduced HDAC1 expression levels at P4. Taken together, these findings establish Tnc as a regulator of microglia function during early postnatal development.