PI3K/akt, JAK/STAT and MEK/ERK pathway inhibition protects retinal ganglion cells via different mechanisms after optic nerve injury.
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).
Luo
Jian-Min
JM
Joint Shantou International Eye Center of Shantou University, Shantou, China.
Cen
Ling-Ping
LP
Zhang
Xin-Mei
XM
Chiang
Sylvia Wai-Yee
SW
Huang
Yao
Y
Lin
Dusheng
D
Fan
You-Ming
YM
van Rooijen
Nico
N
Lam
Dennis Shun Chiu
DS
Pang
Chi Pui
CP
Cui
Qi
Q
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000473:pathology; D019771:Axotomy; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004002:Clodronic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D007150:Immunohistochemistry; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D020221:Optic Nerve Injuries / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D012165:Retinal Ganglion Cells / Q000502:physiology*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D002070:Butadienes; D002867:Chromones; D004002:Clodronic Acid; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D053612:Janus Kinases; D009025:Morpholines; D018696:Neuroprotective Agents; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D051057:Proto-Oncogene Proteins c-akt; D050791:STAT Transcription Factors; D020032:Tyrphostins; C113580:U 0126; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C093555:LY 303511; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one