Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration
Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration
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DOI：
10.1073/pnas.1423221112
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发表时间：
2015-02-24
影响因子：
11.1
通讯作者：
Giger, Roman J.
中科院分区：
文献类型：
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作者：
Baldwin, Katherine T.;Carbajal, Kevin S.;Giger, Roman J.
先天免疫可以促进神经系统再生，但潜在的细胞和分子机制尚不清楚。在这里，我们表明，眼内注射脂多糖（LPS）（一种细菌细胞壁成分）或真菌细胞壁提取物酵母聚糖都会导致血液来源的骨髓细胞在玻璃体内快速且可比较地积累。然而，当与眼眶后视神经挤压损伤相结合时，切断的视网膜神经节细胞（RGC）轴突的长时间生长仅发生在注射酵母聚糖的小鼠中，而不会发生在注射LPS的小鼠中。在缺乏模式识别受体 dectin-1 但缺乏 Toll 样受体-2 (TLR2) 的小鼠中，酵母聚糖介导的 RGC 再生大大减少。 dectin-1 和 TLR2 的联合缺失完全阻断了酵母聚糖的再生作用。在视网膜中，dectin-1 由小胶质细胞和树突状细胞表达，但 RGC 不表达。 Dectin-1 也存在于玻璃体中积聚的血液来源的骨髓细胞上。与酵母聚糖相比，眼内注射 dectin-1 配体凝胶多糖 [β(1, 3)-葡聚糖的颗粒形式] 可促进 WT 小鼠的视神经再生，但在 dectin-1(-/-) 小鼠中则不然。颗粒状 β(1, 3)-葡聚糖可增加体内骨髓细胞中 Erk1/2 MAP 激酶信号传导和 cAMP 反应元件结合蛋白 (CREB) 的激活。 dectin-1 下游效应器 caspase 募集域 9 (CARD9) 的缺失会阻止 CREB 激活并减弱 β(1, 3)-葡聚糖的轴突再生作用。对 dectin-1(-/-)/WT 骨髓嵌合小鼠的研究表明，视网膜驻留免疫细胞和骨髓衍生细胞都需要 dectin-1，以促进 β(1, 3)-葡聚糖诱导视神经再生。总的来说，这些研究确定了先天免疫如何修复受损中枢神经系统神经元的分子框架。
Innate immunity can facilitate nervous system regeneration, yet the underlying cellular and molecular mechanisms are not well understood. Here we show that intraocular injection of lipopolysaccharide (LPS), a bacterial cell wall component, or the fungal cell wall extract zymosan both lead to rapid and comparable intravitreal accumulation of blood-derived myeloid cells. However, when combined with retro-orbital optic nerve crush injury, lengthy growth of severed retinal ganglion cell (RGC) axons occurs only in zymosan-injected mice, and not in LPS-injected mice. In mice deficient for the pattern recognition receptor dectin-1 but not Toll-like receptor-2 (TLR2), zymosan-mediated RGC regeneration is greatly reduced. The combined loss of dectin-1 and TLR2 completely blocks the proregenerative effects of zymosan. In the retina, dectin-1 is expressed by microglia and dendritic cells, but not by RGCs. Dectin-1 is also present on blood-derived myeloid cells that accumulate in the vitreous. Intraocular injection of the dectin-1 ligand curdlan [a particulate form of beta(1, 3)-glucan] promotes optic nerve regeneration comparable to zymosan in WT mice, but not in dectin-1(-/-) mice. Particulate beta(1, 3)-glucan leads to increased Erk1/2 MAP-kinase signaling and cAMP response element-binding protein (CREB) activation in myeloid cells in vivo. Loss of the dectin-1 downstream effector caspase recruitment domain 9 (CARD9) blocks CREB activation and attenuates the axon-regenerative effects of beta(1, 3)-glucan. Studies with dectin-1(-/-)/WT reciprocal bone marrow chimeric mice revealed a requirement for dectin-1 in both retina-resident immune cells and bone marrow-derived cells for beta(1, 3)-glucan-elicited optic nerve regeneration. Collectively, these studies identify a molecular framework of how innate immunity enables repair of injured central nervous system neurons.