Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Cell Death Differ. 2013 Feb;20(2):270-80. doi: 10.1038/cdd.2012.122. Epub 2012 Sep 14.
Optic nerve injury (ONI) induces retinal ganglion cell (RGC) death and optic nerve atrophy that lead to visual loss. Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase and has an important role in stress-induced RGC apoptosis. In this study, we found that ONI-induced p38 activation and RGC loss were suppressed in ASK1-deficient mice. Sequential in vivo retinal imaging revealed that post-ONI treatment with a p38 inhibitor into the eyeball was effective for RGC protection. ONI-induced monocyte chemotactic protein-1 production in RGCs and microglial accumulation around RGCs were suppressed in ASK1-deficient mice. In addition, the productions of tumor necrosis factor and inducible nitric oxide synthase in microglia were decreased when the ASK1-p38 pathway was blocked. These results suggest that ASK1 activation in both neural and glial cells is involved in neural cell death, and that pharmacological interruption of ASK1-p38 pathways could be beneficial in the treatment of ONI.
视神经损伤（ONI）会导致视网膜神经节细胞（RGC）死亡和视神经萎缩，从而导致视力丧失。凋亡信号调节激酶 1（ASK1）是一种进化上保守的丝裂原活化蛋白激酶（MAPK）激酶激酶，在应激诱导的 RGC 凋亡中具有重要作用。在这项研究中，我们发现 ASK1 缺陷型小鼠中 ONI 诱导的 p38 激活和 RGC 损失受到抑制。体内视网膜成像显示，ONI 后眼球内给予 p38 抑制剂对 RGC 保护有效。ASK1 缺陷型小鼠中，ONI 诱导的 RGC 中单核细胞趋化蛋白-1 产生和 RGC 周围小胶质细胞聚集受到抑制。此外，当阻断 ASK1-p38 通路时，小胶质细胞中的肿瘤坏死因子和诱导型一氧化氮合酶的产生减少。这些结果表明，神经和神经胶质细胞中的 ASK1 激活参与了神经细胞死亡，而药理学阻断 ASK1-p38 通路可能有助于治疗 ONI。
