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首页> 外文期刊>The European Journal of Neuroscience >PI3K/akt, JAK/STAT and MEK/ERK pathway inhibition protects retinal ganglion cells via different mechanisms after optic nerve injury.
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PI3K/akt, JAK/STAT and MEK/ERK pathway inhibition protects retinal ganglion cells via different mechanisms after optic nerve injury.

机译：视神经损伤后，PI3K / akt，JAK / STAT和MEK / ERK途径抑制可通过不同机制保护视网膜神经节细胞。

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摘要

Recently we unexpectedly found that PI3K/akt, JAK/STAT and MEK/ERK pathway inhibitors enhanced retinal ganglion cell (RGC) survival after optic nerve (ON) axotomy in adult rat, a phenomenon contradictory to conventional belief that these pathways are pro-survival. In this study we showed that: (i) the RGC protection was pathway inhibition-dependent; (ii) inhibition of PI3K/akt and JAK/STAT, but not MEK/ERK, activated macrophages in the eye, (iii) macrophage removal from the eye using clodronate liposomes significantly impeded PI3K/akt and JAK/STAT inhibition-induced RGC survival and axon regeneration whereas it only slightly affected MEK/ERK inhibition-dependent protection; (iv) in the absence of recruited macrophages in the eye, inhibition of PI3K/akt or JAK/STAT did not influence RGC survival; and (v) strong PI3K/akt, JAK/STAT and MEK/ERK pathway activities were located in RGCs but not macrophages after ON injury. In retinal explants, in which supply of blood-derived macrophages is absent, MEK/ERK inhibition promoted RGC survival whereas PI3K/akt or JAK/STAT inhibition had no effect on RGC viability. However, MEK/ERK inhibition exerted opposite effects on the viability of purified adult RGCs at different concentrations in vitro, suggesting that this pathway may be bifunctional depending on the level of pathway activity. Our data thus demonstrate that inhibition of the PI3K/akt or JAK/STAT pathway activated macrophages to facilitate RGC protection after ON injury whereas the two pathways per se did not modulate RGC viability under the injury conditions (in the absence of the pathway activators). In contrast, the MEK/ERK pathway inhibition protected RGCs via macrophage-independent mechanism(s).
机译：最近，我们意外地发现，PI3K / akt，JAK / STAT和MEK / ERK途径抑制剂可增强成年大鼠视神经（ON）轴突切开术后视网膜神经节细胞（RGC）的存活率，这种现象与传统观点相反，即这些途径是促存活的。在这项研究中，我们表明：（i）RGC保护是依赖途径抑制的; （ii）抑制PI3K / akt和JAK / STAT，但不抑制MEK / ERK激活的眼巨噬细胞，（iii）使用氯膦酸盐脂质体从眼中清除巨噬细胞会显着阻碍PI3K / akt和JAK / STAT抑制诱导的RGC存活轴突再生，而对MEK / ERK抑制依赖性保护的影响很小。 （iv）在眼睛中没有募集的巨噬细胞的情况下，PI3K / akt或JAK / STAT的抑制不影响RGC的存活; （v）强烈的PI3K / akt，JAK / STAT和MEK / ERK通路活性位于ON损伤后的RGC中，而不位于巨噬细胞中。在缺少血液来源的巨噬细胞供应的视网膜外植体中，MEK / ERK抑制作用促进了RGC的存活，而PI3K / akt或JAK / STAT抑制作用对RGC的生存能力没有影响。但是，MEK / ERK抑制在体外不同浓度下对纯化的成年RGC的生存力产生相反的影响，这表明该途径可能是双功能的，具体取决于途径活性的水平。因此，我们的数据表明，对PI3K / akt或JAK / STAT通路的抑制可激活巨噬细胞，以促进ON损伤后的RGC保护，而在损伤条件下（在没有通路激活剂的情况下），这两个通路本身均未调节RGC的活力。相反，MEK / ERK途径抑制通过独立于巨噬细胞的机制保护了RGC。

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