PI3K/akt, JAK/STAT and MEK/ERK pathway inhibition protects retinal gaglion cells via different mechanisms after optic nerve injury

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Zhang, Xinmei, Luo, Jian-Min, Cen, Ling-Ping, Chiang, Sylvia Wai-Yee, Huang, Yao, Lin, Dusheng, Fan, You-Ming, van Rooijen, Nico , Lam, Dennis Shun-Chiu, Pang, Chi-Pui and Qi, Cui (2007) PI3K/akt, JAK/STAT and MEK/ERK pathway inhibition protects retinal gaglion cells via different mechanisms after optic nerve injury. European Journal Of Neuroscience, 26 (4). pp. 828-842. ISSN 1460-9568


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 prosurvival. 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).

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Item type Article
URI https://vuir.vu.edu.au/id/eprint/21757
DOI 10.1111/j.1460-9568.2007.05718.x
Official URL http://onlinelibrary.wiley.com/doi/10.1111/j.1460-...
Subjects Historical > FOR Classification > 1103 Clinical Sciences
Historical > FOR Classification > 1109 Neurosciences
Historical > FOR Classification > 1113 Optometry and Ophthalmology
Historical > Faculty/School/Research Centre/Department > School of Sport and Exercise Science
Keywords JAK⁄STAT, macrophage, MEK⁄ERK, neuronal survival, pathway inhibition, PI3K⁄akt, macrophage activation, RGC survival, axon regeneration, gene expression, retina
Citations in Scopus 56 - View on Scopus
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