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PI3K/akt, JAK/STAT and MEK/ERK pathway inhibition protects retinal ganglion cells via different mechanisms after optic nerve injury
Author(s) -
Luo JianMin,
Cen LingPing,
Zhang XinMei,
Chiang Sylvia Waiyee,
Huang Yao,
Lin Dusheng,
Fan YouMing,
Van Rooijen Nico,
Lam Dennis Shun Chiu,
Pang Chi Pui,
Cui Qi
Publication year - 2007
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2007.05718.x
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , mapk/erk pathway , retinal ganglion cell , jak stat signaling pathway , microbiology and biotechnology , chemistry , ly294002 , biology , cancer research , signal transduction , retinal , biochemistry , tyrosine kinase
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).