Glaucoma and optic nerve repair

Article (PDF Available)inCell and Tissue Research 353(2) · March 2013with146 Reads
DOI: 10.1007/s00441-013-1596-8 · Source: PubMed
Abstract
Glaucoma is a leading cause of irreversible blindness worldwide and causes progressive visual impairment attributable to the dysfunction and death of retinal ganglion cells (RGCs). Progression of visual field damage is slow and typically painless. Thus, glaucoma is often diagnosed after a substantial percentage of RGCs has been damaged. To date, clinical interventions are mainly restricted to the reduction of intraocular pressure (IOP), one of the major risk factors for this disease. However, the lowering of IOP is often insufficient to halt or reverse the progress of visual loss, underlining the need for the development of alternative treatment strategies. Several lines of evidence suggest that axonal damage of RGCs occurs primary at the optic nerve head, where axons appear to be most vulnerable. Axonal injury leads to the functional loss of RGCs and subsequently induces the death of the neurons. However, the detailed molecular mechanism(s) underlying IOP-induced optic nerve injury remain poorly understood. Moreover, whether glaucoma pathophysiology is primarily axonal, glial, or vascular remains unclear. Therefore, protective strategies to prevent further axonal and subsequent soma degeneration are of great importance to limit the progression of sight loss. In addition, strategies that stimulate injured RGCs to regenerate and reconnect axons with their central targets are necessary for functional restoration. The present review provides an overview of the context of glaucoma pathogenesis and surveys recent findings regarding potential strategies for axonal regeneration of RGCs and optic nerve repair, focusing on the role of cytokines and their downstream signaling pathways.
REVIEW
Glaucoma and optic nerve repair
Heike Diekmann & Dietmar Fischer
Received: 1 November 2012 /Accepted: 21 February 2013
#
Springer-Verlag Berlin Heidelberg 2013
Abstract Glaucoma is a leading cause of irreversible blind-
ness worldwide and causes progressive visual impairment
attributable to the dysfunction and death of retinal ganglion
cells (RGCs). Progression of visual field damage is slow and
typically painless. Thus, glaucoma is often diagno sed after a
substantial percentage of RGCs has been damaged. To date,
clinical interventions are mainly restricted to the reduction
of intraocular pressure (IOP), one of the major risk factors
for this disease. However, the lowering of IOP is often
insufficient to halt or reverse the progress of visual loss,
underlining the need for the development of alternative
treatment strategi es. Several lines of evidence suggest that
axonal damage of RGC s occurs primary at the optic nerve
head, where axons appear to be most vulnerable. Axonal
injury leads to the functional loss of RGCs and subsequently
induces the death of the neurons. However, the detailed
molecular mechanism(s) underlying IOP-induced optic
nerve injury remain poorly understood. Moreover, whether
glaucoma pathophysiology is primarily axonal, glial, or
vascular remains unclear. Therefore, protect ive strategies
to prevent further axonal and subsequent soma degeneration
are of great importance to limit the progression of sight loss.
In addition, strategies that stimulate injured RGCs to regen-
erate and reconnect axons with their central targets are
necessary for functional restoration. The present review pro-
vides an overview of the context of glaucoma pathogenesis
and surveys recent findings regarding potential strategies for
axonal regeneration of RGCs and optic nerve repair, focus-
ing on the role of cytokines and their downstream signaling
pathways.
Keywords Glaucoma
.
Neuroprotection
.
Axon
regeneration
.
Inflammatory stimulation
.
CNTF
Introduction
Glaucoma is a generic term for a group of heterogeneous
ocular neuropathies that eventually lead to gradual axonal
degeneration in the optic nerve and progressive loss of
retinal ganglion cells (RGCs). Glaucoma is a leading cause
of visual impairment and irreversible blindness worldwide,
and an estimated 80 million people will be affected in 2020
(Quigley and Broman 2006). Furthermore, another 100
million people have increased intraocular press ure (IOP),
which is a well-known risk factor for glaucoma (Thylefors
and Negrel 1994; World Health Organisation 1997).
Glaucoma is more common in the elderly, an d thus its
prevalence is anticipated to increase further with higher life
expectancy of humans in the future (Quigley and Vitale
1997). Progression of glaucoma is slow and typically pain-
less, so that patients commonly do not experience any
problems until significant visual loss becomes ev ident
(Quigley 2011). As in most neurodegenerative diseases,
the cellular pathophysiology of glaucoma is poorly under-
stood, reflecting its complex multifactorial aetiology.
Axonal damage in glaucoma
Clinical observations in humans and various data from
animal experiments point to the optic nerve head (ONH)
with the laminar region as being the initial site of axonal
damage in glaucoma (Fig. 1; Goldberg 2011; Nickells et al.
2012). In glaucomatous rodents, regions of RGC damage
are sharply del imited and often match the path of axon
bundles, appearing as pie- or fan-shaped wedges radiating
from the ONH to the periphery (Jakobs et al. 2005; Schlamp
et al. 2006; Howell et al. 2007; Salinas-Navarro et al. 2010;
The work of the authors was supported by the German Research
Foundation.
H. Diekmann
:
D. Fischer (*)
Department of Neurology, Experimental Neurology,
Heinrich Heine University, Merowingerplatz 1a,
40225 Düsseldorf, Germany
e-mail: Dietmar.Fischer@uni-duesseldorf.de
Cell Tissue Res
DOI 10.1007/s00441-013-1596-8
Soto et al. 2011). Because RGC axons do not remain in
highly organized bundles after passage through the lamina,
this pattern matches localized damage to axon bundle s at the
glial lamina (Howell et al. 2007). Moreover, in Bcl-2asso-
ciated X pr ot ei n (BA X)- defi ci en t, ch roni c g lauc om at ous
DBA/2J mic e, which exhibit prolonged RGC survival after
axonal i njury (Libby et al. 20 05; Semaan et al. 2010),
axonal segments within and distal to the laminar region
rapidly degenerate, whereas proximal segments attached to
surviving RGC somas remain intact (Howell et al. 2007),
similar to the findings after acute optic nerve crush. These
results provide strong experimental evidence for an early
axonal insult occurring within or close to the laminar region
in glaucoma. Glaucomatous DBA/2J mice carrying the Wld
S
allele, which is known to slow or prevent axon degenera-
tion, show less RGC soma degeneration and retention of
activity (Howell et al. 2007). Therefore, measures pre-
serving the integrity of axons might also prevent RGC
degeneration in glaucoma (Quigley et al. 1981; Nickells
et al. 2012).
Increased IOP has been modeled to increase the strain
within and across the lamina region, the site at which the
sclera is morphologically altered to allow RGC axons to exit
the eye (Fig. 1; Burgoyne 2011). Consistently, morpholog-
ical damage and focal axonal swelling are first detectable in
the lamina region in human glaucoma (Quigley et al. 1983),
in experimental glaucoma in primates (Anderson and
Hendrickson 1974; Quigley and Anderson 1976), and in
chronic glaucoma in DBA/2J mic e (Howell et al. 2007).
However, the molecular or cellular mechanism(s) underly-
ing optic nerve injury remain poorly understood (Weber et
al. 2008;Goldberg2011). On the one hand, pressure-
induced distortions of the collagenous plates in the lamina
cribrosa of humans have been suggested to damage RGC
axons mecha nically (Morgan et al. 1998) and/or to compress
blood vessels that supply the ONH, causing local ischemia
(Findl et al. 1997; Pillunat et al. 1997). Nevertheless, ro-
dents that lack collagenous plates in the lamina can also
develop glaucoma (Danias et al. 2003; Mabuch i et al. 2004;
Jakobs et al. 2005; Filippopoulos et al. 2006; Schlamp et al.
2006; Howell et al. 2007). Then again, activated ONH glia
could release potent neurotoxic factors, such as tumor ne-
crosis factor-α and nitric oxide, causing localized axonal
damage in the ONH region (Fig. 1; Neufeld et al. 1997).
The laminar region has high metabolic demands, which is
correlated with increased cyclooxygenase activity a nd a
Fig. 1 Pathological features of
glaucoma. a Representation of a
mammalian eye with retinal
ganglion cells (RGC) projecting
axons to the optic nerve.
Glaucoma is often characterized
by increased intraocular
pressure (IOP) and localized
changes at the optic nerve head,
including reduced axonal
transport, increased glial
activation and metabolic stress,
local ischemia and endoplasmic
reticulum (ER) stress, leading to
axonal damage in the laminar
region. b Axons distal to the
injury degenerate, whereas
proximal axons survive, but fail
to regenerate. Ultimately, RGCs
in the retina die by apoptosis,
thereby inducing partial visual
field loss
Cell Tissue Res
high density of voltage-gated sodium channels and mito-
chondria in this unmyelinated portion of the ONH compared
with the myelinated optic nerve (Minckler et al. 1977;
Barron et al. 2004; Morgan 2004). Therefore , axon seg-
ments in the lamina are probably vulnerable to metabolic
stress (Yu-Wai-Man et al. 2011). High IOP has been shown
to decrease ATP levels in DBA/2J optic nerves (Baltan et al.
2010) and to alter mitochondrial functions (Ju et al. 2008), a
finding als o described in glaucoma p atients (Abu-Amero
and Bosley 2006). The hydrolysis of ATP is, among others,
required for axonal transport, and the disruption of axonal
transport has been descr ibed to occur early in glaucoma
(Anderson and Davis 1996; Anderson 1999; Goldberg
2011). Both anterograde and retrograde transport are
compromised in the ONH of monkeys with experimental
glaucoma (Anderson and Hendrickson 1974; Radius and
Anderson 1981; Dandona et al. 1991), and organelles accu-
mulate in both the prelaminar and postlaminar regions of
the ONH (Gaasterland et al. 1978). Experimentally ele-
vated IOP also reportedly alters axonal transport in rats
(Pease et al. 2000; Quigley et al. 2000; Salinas-Navarro
et al. 2010; Chidlow et al. 2011), and the first signs of
axonal damage in glaucomatous DBA/2J mice comprise
the localized accumulation of organelles in some, but not
all, RGC axons in the glial lamina (Jakobs et al. 2005;
Howell et al. 2007).
Even transient and modest IOP elevations for 24 h can
induce axonal transport defects at the lamina in experimen-
tal animals (Levy 1974; Quigley and Anderson 1976;
Minckler et al. 1977). Transport normalizes after IOP reduc-
tion, indicating that disturbed axonal transport precedes
glaucoma induced RGC damage, and that early axonal
dysfunction might be reversible (Buckingham et al. 2008).
Indeed, electrophysiologic measurements of RGC function
demonstrate recovery after acute pressure lowering in
glaucomatous patients. However, the mechanism by which
increased IOP results in the disruption of axonal transpo rt is
so far not understood. Axonal transport deficits could alter
cellular homeostasis and evoke further dysregulation of
cellular processes in RGC somas (Fig. 1; Abe and Cavalli
2008). Accordingly, increased free radicals and reactive
oxygen species have been found in glaucomatous eyes. In
addition, hyper-phosphorylated tau a nd other abnormally
folded proteins have been reported to accumulate in retinas
of glaucoma patients (Gupta et al. 2008). This could cause
endoplasmic reticulum stress, which is indeed detected in
RGCs after IOP elevation (Shimazawa et al. 2007).
Nevertheless, the blockage of retrograde transport has been
argued to occur too slowly to signal damage to RGC somas,
as alterations in protein phosphorylation and gene expres-
sion occur within 30 min after acute optic nerve damage
(Lukas et al. 2009). Irrespective of the underlying patho-
physiology of glaucoma, optic nerve axons are damaged,
and RGC somas ultimately die by apoptosis, leading to
irreversible visual loss (Corredor and Goldberg
2009).
Neuroprotection in glaucoma
A long-standing goal of glaucoma treatment is to decelerate
and/or prevent the progression of RGC death, so that visual
function is maintained for as long as possible (Chang and
Goldberg 2012). As RGC survival depends on neurotrophic
support, the identification of ne uroprote ctive factor s has
received much attention. The classic neurotrophin family
comprises four diffusible trophic proteins, namely nerve
growth factor (NGF), brain-derived neurotrophic factor
(BDNF), neurotrophin 4/5 (NT4/5), and neurotrophin 3
(NT3), which bind to specific tyrosine kinase receptors
(TrK-A, -B, and -C; Ebadi et al. 1997). Among these,
BDNF and NT4/5 have been reported to confer significant
neuroprotection to injured RGCs (Mey and Thanos 1993;
Cohen et al. 1994; Mansour-Robaey et al. 1994; Pernet and
Di Polo 2006). BDNF is released by RGC target neurons in
the brain, binds to TrK-B on axonal termini and is
transported back to the RGC somas. This retrograde trans-
port of neurotrophic factors might be reduced upon axonal
damage in glaucoma. Indeed, Trk-B receptors with bound
BDNF accumulate in the lamina region of rats with exper-
imental glaucoma (Pease et al. 2000), and the application of
exogenous BDNF protects RGCs in animal glaucoma
models (Di Polo et al. 1998; Cheng et al. 2002). RGCs also
express several receptors of other trophic factors such as
fibroblast growth factor receptor (FGFR1), glial-cell-
derived neurotrophic factor (GDNF) family receptor α 1
(Ret/GFRα1), hepatocyte growth factor receptor (HGFR),
and granulocyte-macrophage colony-stimulating-factor re-
ceptor (GM-CSF-α-R). Accordingly, intravitreal application
of FGF2, GDNF, HGF, and GM-CSF reportedly increase the
survival of mature RGCs upon optic nerve injury (Bahr et al.
1989; Koeberle and Ball 1998; Schallenberg et al. 2009;
Tonges et al. 2011). However, these neuroprotective effects
are transient and only delay the progress of neuronal degen-
eration rather than preventing it (Di Polo et al. 1998; Leaver
et al. 2006), possibly because RGCs become less responsive
to trophic factors after injury (Goldberg and Barres 2000).
Electrical stimulation of RGCs or pharmacologi cal increase
of intracellular cAMP levels greatly potentiates the pro-
survival effects of neurotrophic factors and might enhance
their efficacy (Corredor and Goldberg 2009).
In this context, the use of stem cells might be promising.
Stem cells cannot yet be transformed into RGCs and stim-
ulated to grow axonal connections from the eye to the brain.
Nevertheless, they may, in the short term, at least provide
dysfunctional RGCs, which are still alive in glaucoma, with
survival and growth factors. Accordingly, intravitreally
Cell Tissue Res
injected stem cells have been shown to enhance RGC axon
and cell body survival in a preclinical model of glaucoma
(Johnson et al. 2010).
Animal models of glaucoma have demonstrated that
RGC dea th occurs only relatively late in the disease
(Goldberg 2011). Acute elevation of IOP first slows axonal
transport before axons degenerate. However, RGC somas
can persist for prolonged periods in a stressed state prior to
apoptotic degeneration (Jakobs et al. 2005; Libby et al.
2005;Howelletal.2007;Sotoetal.2008). Increased
survival per se is, however, not sufficient to enable RGCs
to regrow injured axons. For example, mice overexpressing
the anti-apoptotic protein Bcl-2 show almost no RGC
death after axotomy, but do not regenerate axons into the
optic nerve (Chierzi et al. 1999; Inoue et al. 2002).
Therefore, merely prevent ing RGC apoptosis after axonal
damage will not enhance the regrowth of injured axons.
Ideal glaucoma therapies should therefore also encourage
axon regeneration to re-establish connections from the eye
to the brain.
Regeneration in glaucoma
Despite the need for strategies to promote RGC axon regen-
eration in glaucoma, clinically established treatments to
repair damaged axonal connections in the visual system
are currently not available. Regenerative failure has been
mainly attributed to the growth-inhibitory environment of
the optic nerve and the insufficient intrinsic ability of mature
RGCs to regrow axons.
The mature optic nerve per se has been described as a
poor substrate for axonal growth. Receptors on growing
axons have been shown to interact with inhibitory molecules
in their environment, leading to the destabilization of the
actin cytoskeleton in filopodia and lamellipodia and the
subsequent collapse of the growth cone (Yiu and He 2006;
Berry et al. 2008). A number of these inhibitory proteins
have been identified, such as Nogo, myelin-associated gly-
coprotein (MAG), and oligodendrocyte-myelin glycoprotein
(OMgp; McKerracher et al. 1994; Chen et al. 2000; Wang et
al. 2002b). Even though these three myelin-associated pro-
teins are structurally heterogeneous, they all bind to the
Nogo receptor (NgR; Domeniconi et al. 2002; Wang et al.
2002a). The glycosyl-phosphatidyl inositol (GPI)-linked
NgR interacts with p75
NTR
or with TNF r eceptor super-
family, member 19 (TROY) and leucine-rich repeat and Ig
domain containing 1 (LINGO-1) to form functional receptor
complexes (Wang et al. 2002a; Wong et al. 2002; Yamashita
et al. 2002;Mietal.2004). Knockdown or expression of a
dominant negative NgR in RGCs increases optic nerve
regeneration in vivo only with concomitant stimulation of
the intrinsic RGC growth state (Fischer et al. 2004a; Su et al.
2009), indicating that neutralization of myelin inhibition
alone might be insufficient to promote regeneration in the
optic nerve . However, other growth inhibitors or a xonal
receptors might additionally contribute to axon growth in-
hibition in the injured optic nerve. Accordingly, PirB has
recently been described as a dis tinct rece ptor for Nogo ,
MAG, and OMgp (Atwal et al. 2008; Cai et al. 2012). In
addition, inflammation-induced glial scar formation at a lesion
site represents another barrier for axonal regeneration after
traumatic nerve injury (Silver and Miller 2004). Resident
microglia and astrocytes are activated and secrete growth-
inhibitory molecules such as semaphorins, Tenascin-R and
chondroitin sulfate proteoglycans (CSPGs; McKeon et al.
1991; Niederost et al. 1999; Tang 2003). Whether inhibitory
processes and the release of toxic proteins also contribute to
RGC dysfunction and inhibition of axonal regeneration in
glaucoma remains unknown. However, ONH glia release
tissue growth factor-β, which has been shown to induce
CSPG secretion and fibrotic scarring (Lagord et al. 2002;
Logan and Berry 2002), upon increased IOP (Neufeld and
Liu 2003).
RGC signaling pathways that mediate growth inhibition
could be efficient clinical targets for promoting axonal regen-
eration. Several myelin- and glial-associated inhibitory signals
converge on the proteins ras homolog gene A and rho-
associated protein kinase (RhoA, ROCK) to induce growth
cone collapse (Mueller 1999;Lingoretal.2007). Treatment of
acutely injured RGCs with ADP ribosyltransferase C3, an
irreversible RhoA inhibitor, allows severed axons to cross
the lesion site and to grow into the distal nerve segment
(Lehmann et al. 1999; Bertrand et al. 2005). Similarly, treat-
ment of RGCs with specific ROCK inhibitors reduces myelin
and CSPG inhibition in vitro and allows axons to regenerate
beyond the lesion site of the optic nerve in vivo (Lingor et al.
2007, 2008; Ahmed et al.2009). Experimental data from glau-
coma studies have shown that Rho and ROCK inhibitors can
enhance ocular blood flow and increase aqueous humor drain-
age through the trabecular meshwork, thereby decreasing IOP
(Rao and Epstein 2007). Several ROCK inhibitors are cur-
rently being tested in clinical trials for their IOP-lowering
effects, but could also prove useful for enhancing optic nerve
regeneration.
The extension of microtubules during axonal growth de-
pends on the net-polymerization of tubulin dimers.
Microtubule dynamics in growth cones are affected by actin
polymerization and are therefore also indirectly modulated
by RhoA/ROCK signaling (Mimura et al. 2006; Conde and
Caceres 2009). The anti-cancer drug Paclitaxel (Taxol) pro-
motes m icrotubule polymerization at low concentrations
and uncouples their interaction with actin filaments, thereby
improving growth cone motility and decreasing sensitivity
towards growth-inhibitory molecules (Derry et al. 1995,
1997; Sengottuvel et al. 2011
). Consistently, Taxol promotes
Cell Tissue Res
the axonal growth of primary RGCs per se and also on
inhibitory myelin and CSPG substrates in vitro
(Sengottuvel et a l. 2011; Fischer and Leibinger 2012).
Taxol treatment in vivo markedly increases regeneration
after acute optic nerve injury, allowing RGC axons to grow
across the injury site (Sengottuvel et al. 2011). In addition,
glial scar formation is delayed, and CSPG secretion is
reduced at the injury site upon Taxol treatment (Hellal et
al. 2011; Sengottuvel et al. 2011). Whether the application
of low Taxol concentrations might be a promising approach
for glaucoma treatment probably needs to be first investi-
gated by using glaucoma animal models. Because of the
relatively short-term effects of Taxol in comparison with the
long-term progression of most types of chronic glaucoma,
appropriately localized and continuous delivery methods
need to be developed to potentially enhance axon regener-
ation in glaucomatous optic nerves.
Stimulation of RGC growth state
Adult RGCs normally fail to regenerate after acute axonal
injury, and only a few injured neurons re-extend axons in
vitro or in vivo (Vidal-Sanz et al. 1987, 1988; Muller et
al. 2007). However, puncture of the lens capsule induces a
low-gr ade inflam matory response in the eye and trans-
forms axotomized RGCs into a robust regenerative state,
which is characterized by altered gene expression (Fischer
et al. 2000, 2004b; Leon et al. 2000). As a result, RGC
death is markedly delayed, and lengthy axons a re
regenerated into the inhibitory environment of a crushed
optic nerve (Fischer et al. 2000, 2001; Leon et al. 2000).
Thus, lens injury exerts neuroprotective, axon-growth-
promoting, and disinhibitory effects. Nevertheles s, lens
injury as a treatment approach for glaucoma in humans
is rather inappropriate, as it rapidly promotes cataract
formation. Therefore, the identification of the molecular
basis of this positive inflammatory respon se might identify
more realistic targets for the translation to human glauco-
ma treatment.
Intravitreal injection of β-orγ-crystallins or of toll-like
receptor 2 agonists, such as zymosan or Pam
3
Cys, have
been shown to mimic fully the beneficial effects of lens
injury on axonal regeneration (Leon et al. 2000; Fischer et
al. 2008;Hauketal.2010). The induced inflammatory
response is characterized by macrophages infiltrating the
eye and by the activation of retinal astrocytes and Müller
cells to secrete the cytokines ciliary neurotrophic factor
(CNTF) and leukemia inhibitory factor (LIF; Muller et al.
2007; Fischer 2008; Leibinger et al. 2009). The key role of
CNTF and LIF in promoting the beneficial effects of in-
flammatory stimulation (IS) upon lens injury has been dem-
onstrated i n experimental studies of knockout mice.
Neuroprotective and axon growth-promoting effects of IS
are absent in mice deficient for CNTF and LIF (Leibinger et
al. 2009). In vitro, CNTF and LIF each potently enhance
RGC neurite outgrowth, even in the absence of increased
cyclic adenosine monophosphate (cAMP) levels (Jo et al.
1999; Muller et al. 2007, 2009; Leibinger et al. 2009;
Ahmed et al. 2010; Sengottuvel et al. 2011). Nevertheless,
cAMP elevation potentiates the benefi cial effects of CNTF
and IS (Cui et al. 2003; Park et al. 2004; Muller et al. 2007,
2009). However, the beneficial effects of intravitreally ap-
plied recombinant CNTF are less pronounced than those of
IS (Muller et al. 2007, 2009; Lingor et al. 2008), possibly
becau se of the short half-life of exogenous CNT F in the
vitreous. Consistently, a constant CNTF supply via viral ex-
pression results in signifi cantly greater regeneratio n, with
axons reaching the optic c hiasm 5 weeks a fter an intra-
orbital optic nerve crush (Leaver et al. 2006; Hellstrom et al.
2011). Because of these promising experimental results,
CNTF is going to be tested in clinical trials for human glau-
coma, for example, by using encapsulated CNTF-expressing
cells for drug delivery (clinicaltrials.gov NCT01408472).
Axon growth stimulatory signaling cascades
In addition to the direct application of IS mediators such as
CNTF, the manipulation of downstream signaling cascades
of these cytokines might be a promising approach to in-
crease axonal regeneration in glaucoma. CNTF an d LIF
belong to the family of interleukin-6 (IL-6)-type cytokines.
These cytokines mediate their effects through the signal
transducing receptor glycoprotein 130 (gp130) and, in case
of CNTF and LIF, the LIF-receptor (LIFR; Fig. 2; Heinrich
et al. 2003). LIF directly interacts with LIFR, which subse-
quently forms a heterodimeric complex with gp130. CNTF
first binds to the CNTF-receptor α (CNTFRα), which then
recruits the signaling subunits LIFR and gp130 to form a
ternary receptor complex (Fig. 2). All these receptor com-
ponents are expressed by mature and axotomized RGCs
(Muller et al. 2007; Leibinger et al. 2009, 2012), suggesting
a direct effect of these cytokines on RGCs (Sarup et al.
2004). Upon cytokine stimulation, LIFR and gp130 associ-
ate with Janus-kinases (JAK1, JAK2, and TYK2) and be-
come tyrosine-phosphorylated (Fig. 2; Heinrich et al. 2003).
The phosphorylated receptors serve a s dock ing sites f or
signal transducer and activator of transcription (STAT;
mainly STAT3) and protein tyrosine phosphatase SHP2
(Rane and Reddy 2000; Muller et al. 2007). In turn,
STAT3 monomers become phosphorylated, dimerize, and
transloc ate into the nucleus to activate the expression of
genes with STAT3 response elements (Fig. 2; Stahl et al.
1994; Hemmann et al. 1996). Phosphor ylated SHP2, on the
other hand, activates the mitogen-activated protein
Cell Tissue Res
Fig. 2 Representation of signaling pathways upon inflammatory stim-
ulation (IS). Binding of interleukin-6 (IL-6)- type cytokines ciliary
neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF)to
their receptors (CNTFR, LIFR, and glycoprotein 130 [gp130]) activates
Janus-kinases (JAK), which then either phosphorylate the transcription
factor signal transducer and activator of transcription-3 (STAT3; JAK2)
or activate the protein tyrosine phosphatase SHP2 (JAK1). Phosphor-
ylated STAT3 forms dimers, which translocate into the nucleus to
initiate STAT3-response-element-dependent gene expression. Phos-
phorylated SHP2 activates the mitogen-activated protein kinase
(MAPK)/extracellular signal regulated kinase and phosphoinositid-3-
kinase (PI3K/Akt) signaling pathways. PI3K converts phos-
phatidylinositol-(4,5)-bisphosphate (PIP2) into phosphatidylinositol-
(3,4,5)-trisphosphate (PIP3), which stimulates phosphatidylinositol-
dependent kinase 1/2 (PDK1/2) to activate Akt. Phosphatase and tensin
homolog (PTEN) counteracts PI3K by catalyzing the conversion of
PIP3 to PIP2. One of the activated downstream signaling targets of Akt
is the mammalian target of rapamycin (mTOR), whose activation can
be specifically blocked by rapamycin. Activated mTOR inhibits the
E4-binding protein1 (E4-BP1), a repressor of the eukaryotic translation
initiation factor 4E (EIF-4E ). Additionally, S6 Kinase 1 (S6K1) and its
target, the ribosomal protein S6 are also controlled by mTOR. Activat-
ed SHP2 can also inhibit JAK-mediated activation of STAT3, thereby
negatively regulating IL-6-type cytokine signaling. STAT3-induced
gene expression of suppressor of cytokine signaling 3 (SOCS3) also
serves as a negative feedback loop, as it inhibits JAK2 activation.
Further, so far unknown signaling pathways might also be involved
in mediating the neuroprotective and axon growth-promoting effects of
IS
Cell Tissue Res
kinase/extracellular signal regulated kinase (MAPK/ERK)
and phosphoinositid-3 -kin ase (PI3K/Akt) signaling path-
ways (Fukada et al. 1996; Kim and Baumann 1999; Ernst
and Jenkins 2004; Park et al. 2004; Leibinger et al. 2012).
However, neurite outgrowth experiments in cell culture with
pharmacological inhibitors suggest that MAPK/ERK activa-
tion is not directly involved in axon growth stimulation in
RGCs, but rather activates the secretion of CNTF by retinal
Müller cells and astrocytes (Muller et al. 2009). In addition,
activated SHP2 can inhibit the JAK-mediated activation of
STAT3, thereby negatively regulating IL-6-type cytokine
signaling (Fig. 2; Lehmann et al. 2003).
Suppressor of cytokine signa ling 3 (SOCS3) is one of the
genes that is induce d upon JAK/STAT3 activation. SOCS3
acts as a feedback inhibitor for JAK activation, avoiding
excessive STAT3 phosphorylation (Nicholson et al. 2000)
and limiting the physiological consequences of STAT3-
mediated signaling (Shouda et al. 2001;Joetal.2005).
Up-regulation of SOCS3 expression is indeed detected in
axotomized RGCs after IS, reachin g maximal levels
2.5 days post injury (Fischer et al. 2004b). Consistently,
SOCS3-deficient RGCs regenerate axons beyond the lesion
site of a crushe d optic nerve, and the effects of intravitreal
CNTF injections are enhanced in conditional SOCS3 knock-
out mice, confirming SOCS3 as an intrinsic brake for
CNTF-induced axonal regeneration (Smith et al. 20 09;
Sun et al. 2011). In addition, SOCS3 expression is
suppressed by increased cAMP levels (Fig. 2; Park et al.
2009), which might explai n why IL-6-type cytokines and
IS-induced axonal regeneration are enhanced by cAMP-
elevating substan ces (Cui et al. 2003; Muller et al. 2007;
Leibinger et al. 2012). As CNTF expression is up-regulated
upon IOP increase in retinas of glaucomatous rats (Wu et al.
2007), the inhibition of SOCS3 might be sufficient to pro-
mote axonal regeneration in the context of glaucoma.
The PI3K/Akt pathway is negatively regulated by phospha-
tase and tensin homolog (PTEN), which catalyzes the conver-
sion of PIP3 to PIP2 and thereby counteracts the activity of
PI3K (Fig. 2). Genetic deletion of PTEN is reportedly
neuroprotective and potently promotes RGC axon regenera-
tion to an extent similar to IS (Park et al. 2008; Sun et al. 2011).
Further downstream, mammalian target of rapamycin (mTOR)
controls protein expression via S6 Kinase 1 (S6K1) and E4-
binding protein1 (E4-BP1; Fig. 2). Consistently, enhanced
axonal regrowth promoted by PTEN deletion is blocked by
mTOR inhibition. Moreover , the deletion of tuberous sclerosis
complex 1 (TSC1), a negative regulator of mTOR signaling,
constitutively activates mTOR and mimicks the effects of
PTEN deletion (Park et al. 2008). Whether PTEN inhibition
or , for that matter , PI3K/Akt/mTor activation is beneficial in
the context of glaucoma still needs to be investigated.
Interestingly, the clinically established anti-glaucoma drug
Latanoprost has been sh own to promote RGC n eurite
outgrowth in culture via activation of the PI3K/Akt pathway
(Zheng et al. 2011
).
In agreement with the view that mTor activation potently
enhances neuroprotection and axon regeneration, treatment
with IL-6-type cytokines and IS prevents the down-
regulation of mTOR activity in axotomized RGCs
(Leibinger et al. 2012). However, mTOR inhibition by
rapamycin inhibits neither the cytokine-mediated axon out-
growth stimulation in culture nor the neuroprotective effects
of IS in vivo. Instead, rapamycin treatment compromises
long distance, but not short distance, axon regeneration in
the optic nerve following IS, indicating that mTOR activity
is important for sustaining RGCs in an active regenerative
state (Leibinger et al. 2012). In addition, mTOR activity
seems to reduce myelin inhibitory effects. Although
rapamycin does not reduce the axonal growth of cultured
RGCs on a growth-permissive substrate, mTOR inhibition
markedly reduces CNTF-induc ed axonal g rowth on myelin
and CSPGs containing inhibitory substrates (Leibinger et al.
2012). These experimental data suggest that the manipula-
tion of intrins ic growth control pathways will provide new
therapeutic approaches to promote substantial axon regen-
eration in the injured visual system.
Concluding remarks
The lowering of IOP wi ll remain an important aspect of
glaucoma therapy, as it often decelerates the progression of
glaucomatous degeneration. Since the onset and early pro-
gression of glaucoma is asymptomatic, glaucoma is often
diagnosed only after substantial damage to retinal axons has
occurred. However, damage of optic nerve axons currently
leads inevitably to irreversible functional loss, since RGCs are
unable to regenerate axonal connections and subsequently die.
Thus, before ultimate cell death, RGCs mig ht be merely
dysfunctional, possibly opening a treatment window for the
regeneration of injured axons. Research over the last two
decades indicate s that mature RGCs can principa lly be
transformed into an active regenerative state that enables these
neurons to survive injury and to re-grow axons over long
distances into the optic nerve. Molecules and relevant signal-
ing cascades that either limit or facilitate axonal regeneration
have been identified and potentially provide novel therapeutic
targets. Combinatorial treatments that simultaneously delay
RGC death and overcome the growth-inhibitory environment
of the glial scar and optic nerve myelin, together with ap-
proaches promoting axonal growth, have so far yielded the
strongest regeneration in experimental settings. These results
are encouraging, but several milestones still have to be
reached before clinical treatments aiming to improve visual
function can be envisioned for glaucomatous patients.
Importantly, the methods to enhance the number and length
Cell Tissue Res
of regenerating axons need to be further optimized. In addi-
tion, strategies have to be developed to guide and topograph-
ically reconnect axons to their targets in the brain. Moreover,
regenerated axons need to be appropriately re-myelinated in
order to ensure proper function. Finally, these approaches
have to be assessed for their therapeutic suitability in human
patients. Nevertheless, novel therapies might eventually pro-
vide IOP-independent treatments for glaucoma.
Acknowledgments We apologize to all colleagues whose important
work was not included because of space limitations.
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Cell Tissue Res
    • "Glaucoma is a complex neurodegenerative condition characterized by progressive retinal ganglion cell (RGC) death and optic nerve degeneration [1, 2] . Current treatments aim to prevent disease progression by lowering intraocular pressure but do not restore lost visual function, for which development of cell-based therapies would potentially benefit patients affected by severe disease. "
    [Show abstract] [Hide abstract] ABSTRACT: Significance: Müller glia with stem cell characteristics are present in the adult human retina, but they do not have regenerative ability. These cells, however, have potential for development of cell therapies to treat retinal disease. Using a feline model of retinal ganglion cell (RGC) depletion, we have developed cell grafting methods to improve RGC function. Using cellular scaffolds, allogeneic transplantation of Müller glia-derived RGC promoted cell attachment onto the retina and enhanced retinal function, as judged by improvement of the photopic negative and scotopic threshold responses of the electroretinogram. The results suggest that the improvement of RGC function observed may be ascribed to the neuroprotective ability of these cells and indicate that attachment of the transplanted cells onto the retina is required to promote effective neuroprotection.
    Full-text · Article · Dec 2015
    • "However, some degree of axonal regeneration is observed upon induction of cytokine expression by inflammatory stimulation (Fischer et al., 2000; Leibinger et al., 2009 Leibinger et al., , 2013 Hauk et al., 2010), intravitreal application of ciliary neurotrophic factor (CNTF) (Lingor et al., 2008; Müller et al., 2009 ) and virusmediated cytokine expression (Leaver et al., 2006; Pernet et al., 2013). In addition, genetic manipulation of certain signaling cascades, such as phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) have been described to promote axon regeneration (Cai et al., 2001; Gao et al., 2004; Fischer and Leibinger, 2012; Diekmann and Fischer, 2013; Pernet et al., 2013). In particular, genetic deletion of the phosphatase and tensin homolog (PTEN), an opponent of PI3K, potently promotes axon regeneration of RGCs, motor, corticospinal and peripheral neurons (Park et al., 2008; Christie et al., 2010; Liu et al., 2010; Ning et al., 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: The developmental decrease of the intrinsic regenerative ability of the mammalian central nervous system (CNS) is associated with reduced activity of mechanistic target of rapamycin (mTOR) in mature neurons such as retinal ganglion cells (RGCs). While mTOR activity is further decreased upon axonal injury, maintenance of its pre-injury level, for instance by genetic deletion of the phosphatase and tensin homolog (PTEN), markedly promotes axon regeneration in mammals. The current study now addressed the question whether active mTOR might generally play a central role in axon regeneration by analyzing its requirement in regeneration-competent zebrafish. Remarkably, regulation of mTOR activity after optic nerve injury in zebrafish is fundamentally different compared to mammals. Hardly any activity was detected in naïve RGCs, whereas it was markedly increased upon axotomy in vivo as well as in dissociated cell cultures. After a short burst, mTOR activity was quickly attenuated, which is contrary to the requirements for axon regeneration in mammals. Surprisingly, mTOR activity was not essential for axonal growth per se, but correlated with cytokine- and PTEN inhibitor-induced neurite extension in vitro. Moreover, inhibition of mTOR using rapamycin significantly reduced axon regeneration in vivo and compromised functional recovery after optic nerve injury. Therefore, axotomy-induced mTOR activity is involved in CNS axon regeneration in zebrafish similar to mammals, although it plays an ancillary rather than essential role in this regeneration-competent species.
    Full-text · Article · Jun 2015
    • "In the year 2020 it is estimated that more than 80 million people will suffer from a glaucomatous disease worldwide [1]. The molecular pathophysiology of glaucoma is poorly understood, reflecting its complex multifactorial etiology [2]. In regard to their etiology, glaucomas can be sub grouped into primary and secondary glaucomas. "
    [Show abstract] [Hide abstract] ABSTRACT: The aqueous humor (AH) component transforming growth factor (TGF)-β2 is strongly correlated to primary open-angle glaucoma (POAG), and was shown to up-regulate glaucoma-associated extracellular matrix (ECM) components, members of the ECM degradation system and heat shock proteins (HSP) in primary ocular cells. Here we present osteopontin (OPN) as a new TGF-β2 responsive factor in cultured human optic nerve head (ONH) astrocytes. Activation was initially demonstrated by Oligo GEArray microarray and confirmed by semiquantitative (sq) RT-PCR, realtime RT-PCR and western blot. Expressions of most prevalent OPN receptors CD44 and integrin receptor subunits αV, α4, α 5, α6, α9, β1, β3 and β5 by ONH astrocytes were shown by sqRT-PCR and immunofluorescence labeling. TGF-β2 treatment did not affect their expression levels. OPN did not regulate gene expression of described TGF-β2 targets shown by sqRT-PCR. In MTS-assays, OPN had a time- and dose-dependent stimulating effect on the metabolic activity of ONH astrocytes, whereas TGF-β2 significantly reduced metabolism. OPN signaling via CD44 mediated a repressive outcome on metabolic activity, whereas signaling via integrin receptors resulted in a pro-metabolic effect. In summary, our findings characterize OPN as a TGF-β2 responsive factor that is not involved in TGF-β2 mediated ECM and HSP modulation, but affects the metabolic activity of astrocytes. A potential involvement in a protective response to TGF-β2 triggered damage is indicated, but requires further investigation.
    Full-text · Article · Apr 2014
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