炎症・再生　Vol.23 No.1 2003522 Mini Review　Neuroprotection against photoreceptor apoptosis

KKKKKey wey wey wey wey wooooordsrdsrdsrdsrds retinal damage, inflammatory cytokines, chemokines, neuroprotection

Mini Review

Understanding the mechanism of retinal detachment-induced photoreceptor apoptosis: neuroprotectivetreatments for photoreceptor apoptosis

Toru Nakazawa1,＊), Masahiko Shimura2), and Kohji Nishida1)1)Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan2)Department of Ophthalmology, NTT East Japan Tohoku Hospital, Sendai, Japan

In retinal detachment and in several other visual disorders, photoreceptor apoptosis represents the major

cause of vision loss. The mechanisms underlying photoreceptor apoptosis, however, remain elusive. Here,

we review our recent publications on the pathogenesis of retinal detachment-induced photoreceptor apoptosis

and discuss the critical role of monocyte chemoattractant protein-1 (MCP-1) in mediating photoreceptor

apoptosis in an experimental rodent model of retinal detachment. Elevated levels of MCP-1 are found in

vitreous samples from patients with retinal detachment. MCP-1 expression is similarly increased in our

rodent model after retinal detachment, with MCP-1 expression being detected in Muller glia. Moreover,

CD11b-immunopositive macrophages/microglia are recruited into the detached retina. Interestingly, the sup-

pression of MCP-1 with an MCP-1－ blocking antibody or through MCP-1 gene deletion, as in MCP-1－deficient mice, significantly reduces macrophage/microglia infiltration and photoreceptor apoptosis. To in-

vestigate whether MCP-1 contributes to photoreceptor apoptosis by directly affecting photoreceptors or by

indirectly affecting photoreceptors through recruited macrophages/microglia, we examined the effect of

MCP-1 on primary retinal mixed cultures and the induction of retinal detachment in Mac-1 (CD11b/CD18)-

deficient mice. Our data showed that MCP-1 cytotoxicity toward cultured photoreceptors occurs through

resident microglia. Moreover, eliminating macrophage/microglia infiltration in vivo decreases photoreceptor

apoptosis after retinal detachment. Thus, retinal detachment induces increased expression of MCP-1 in

Muller cells and increased infiltration and activation of macrophages/microglia, resulting in photoreceptor

apoptosis. This pathway may be an important therapeutic target for preventing photoreceptor apoptosis in

retinal detachment and other central nervous system diseases that share a common etiology.

Rec.1/24/2008, Acc.6/30/2008, pp522-528

＊Correspondence should be addressed to:Toru Nakazawa, M.D., Ph.D., Department of Ophthalmology, Tohoku University Graduate School of Medicine, 1-1Seiryo-Cho, Aoba-ku, Sendai, Miyagi, 980-8574, Japan. Phone: +81-22-717-7294, Fax: +81-22-717-7298, e-mail:ntoru@oph.med.tohoku.ac.jp

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523Inflammation and Regeneration　Vol.28 No.6 NOVEMBER 2008

Introduction　Retinal detachment, which is characterized by a separation of

the neural retina from the retinal pigment epithelium layer, is

observed as an end-stage symptom of most vitreoretinal diseases,

including diabetic retinopathy, age-related macular degeneration,

and proliferative vitreoretinopathy, all leading to blindness1). Due

to recent advances in surgical techniques, more than 90% of pri-

mary retinal detachments are mechanically recoverable. Despite

the high success rate of mechanical retina reattachment, some-

times the visual prognosis is unsatisfactory, especially in cases

of central retinal (macular) detachment. This unsatisfactory vi-

sual prognosis is most likely due to apoptosis in the photorecep-

tors of detached retina2). Visual acuity depends on macular function;

thus, to obtain the best possible visual prognosis following retinal

reattachment, the macula must be neuroprotected. Examination

of retinal samples harvested during retinal detachment－repair

surgery showed that photoreceptors die 3 days after retinal de-

tachment through apoptosis2). Moreover, the time course of pho-

toreceptor apoptosis is very similar to that in a rodent model of

retinal detachment35). Thus, this animal model of retinal detach-

ment is suitable for examining the pathogenesis of retinal de-

tachment that ultimately leads to photoreceptor apoptosis.

　Zack and colleagues used the rodent model to show that caspase

activation plays an important role in retinal detachment-induced

photoreceptor apoptosis6). However, the upstream extracellular

signals leading to caspase activation and ultimately to photore-

ceptor apoptosis after retinal detachment remains unclear. To

explore the detailed mechanisms of retinal detachment-induced

photoreceptor apoptosis, we have focused our research on the

expression of cytokines, chemokines, and growth factors follow-

ing retinal detachment, because these factors are known to regu-

late caspase activity as well as apoptosis in response to injury.

Indeed, monoclonal antibodies targeting cytokines or growth fac-

tors or small inhibitors of tumor necrosis factor alpha (TNFα)

or vascular endothelial growth factor (VEGF) have proven to be

successful in treating retinal damage and thus have gained much

popularity for use in clinical settings7,8). Understanding the roles

of cytokines and growth factors in retinal detachment will pro-

vide further insights into the mechanisms leading to photorecep-

tor cell death as well as to insights into developing new

neuroprotective treatments for photoreceptors.

　In response to mechanical injury, cytokines/chemokines mainly

recruit inflammatory cells to the damaged area. Animal models

have shown that in several retinal diseases cytokines/chemokines

also induce the migration of leukocytes to damaged areas9-11).

Clinically, anti-inflammatory treatment with corticosteroids against

retinal diseases is effective for treating cytokine/chemokine-

associated inflammation, ischemia, or hyperpermeablity-induced

macular edema12-14). Thus, we focused our examination on the

association between photoreceptor apoptosis and recruited leu-

kocytes via the induction of cytokines/chemokines following

retinal detachment.

　Here, we review our recent findings on the pathogenesis of

retinal detachment-induced photoreceptor apoptosis. We also

discuss possible target molecules revealed in an animal model

of retinal detachment as novel neuroprotective treatments for

photoreceptors. Prevention of retinal detachment-induced pho-

toreceptor apoptosis can improve the prognosis of patients with

retinal detachment.

The distribution and the role of glial cellsin the normal rodent retina　There are four types of glial cells in the normal adult rodent

retina: Muller cells, astrocytes, microglia, and macrophages.

Muller cells have cell bodies in the inner nuclear layer and ex-

tend their processes through the entire retina, from the inner lim-

ited membrane to the outer limited membrane (Fig.1A). Astro-

cytes are located in the most inner part of the retina and optic

nerve head (Fig.1B). In the pathological condition of retina, re-

active Muller cells also expressed the GFAP however, in the

normal retina, GFAP is a specific marker for astrocytes. Resi-

dent microglias are located mainly in the inner plexiform layer

(Fig.1C). Usually few macrophages exist in the normal retina.

Retinal glial cells have various roles. Under normal conditions,

the roles of resident microglia and macrophages, however, re-

main unclear. In the central nervous system (CNS), astrocytes in

particular play an important role in maintaining homeostasis15),

including buffering extracellular K+ and glutamate, regulating

neurotransmitter release, and regulating various other processes.

In the retina, however, Muller cells play a more important role

in retinal homeostasis than retinal astrocytes16,17). Under normal

conditions, Muller cells are key players in the maintenance of

retinal neurons, such as retinal ganglion cells and photoreceptors.

Interactions between retinal glial cellsand monocytes under pathological con-ditions　To date, the mechanisms underlying leukocyte recruitment to

damaged areas in the retina remain unknown. It is also unknown

whether leukocytes play an executive role in photoreceptor

apoptosis or whether their role is to clean up the debris from

dead photoreceptors. One major function of monocytes recruited

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炎症・再生　Vol.23 No.1 2003524

to the subretinal space is to phagocytose photoreceptor debris

after retinal detachment; this phagocytosis occurs through the

integrin αvβ3 or phosphatidylserine receptor18). Monocytes are

detected not only in the subretinal space but also in the outer

plexiform layer (OPL). In fact, monocytes appear in the OPL

before they appear in the subretinal space, with a similar time

course as that of photoreceptor apoptosis. Interestingly, the num-

ber of monocytes recruited to the OPL is greater than that re-

cruited to the subretinal space5). Taken together, these observa-

tions prompted us to focus more closely on the role of these OPL

monocytes in photoreceptor apoptosis: (1) Is monocyte recruit-

ment to the OPL mediated by a chemoattractant system? (2) Are

the OPL monocytes toxic to photoreceptors? To address these

two important questions, we examined changes in cytokine and

chemokine expression following retinal detachment. We also

assessed the effects of suppressing monocyte recruitment after

retinal detachment.

The expression of cytokines, chemokines,and growth factors following retinal de-tachment　Vitreous samples from patients with retinal detachments con-

tain greater levels of cytokines, such as interleukin-1 beta (IL-

1β)19), TNFα19), and monocyte chemoattractant protein-1

(MCP-1)20,21), and growth factors, such as basic fibroblast growth

factor (bFGF)22,23), than samples from patients with a macular

hole or idiopathic premacular fibrosis. Cytokines also play a piv-

otal role in proliferative changes associated with retinal detach-

ment, including Muller cell hypertrophy24), neovascularization,

Mini Review　Neuroprotection against photoreceptor apoptosis

Fig.1 The distribution of retinal glial cells in normalretina

(A) Immunofluorescence image of normal retina stained withan antibody against glutamine synthetase, a Muller cell marker.(B) Immunofluorescence image of normal retina stained withan antibody against GFAP, an astrocyte marker.(C) Immunofluorescence image of normal retina stained withan antibody against CD11b, a microglial cell marker. Yellowarrows indicate signals for each glial cell marker. Nuclei arecounterstained with DAPI (blue). GCL, ganglion cell layer; IPL,inner plexiform layer; INL, inner nuclear layer; OPL, outer plexi-form layer; ONL, outer nuclear layer.

Fig.2 Time courses of cytokine, chemokine,and growth factor responses to retinal de-tachment

(A) Table showing mRNA expression changes (foldincrease) in the detached neural retina 72 hours afterretinal detachment compared to untreated neural retinaas determined by quantitative RT-PCR.(B) Chart showing mRNA expression changes (foldincrease) at various time points. IL-1β , TNFα, and MCP-1expression increased immediately after retinal detachment,whereas bFGF expression increased 24 hours after retinaldetachment.

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525Inflammation and Regeneration　Vol.28 No.6 NOVEMBER 2008

neoplasia, and proliferative vitreoretinopathy (PVR)22,23). These

proliferative changes are often serious complications and are

associated with poor prognoses, even after surgery25). Despite

the association between cytokines and growth factors with PVR

and photoreceptor death, the mechanisms that induce cytokine

release and their roles in retinal detachment are largely unex-

plored. In a rodent model of retinal detachment, we showed that

IL-1β, TNFα, MCP-1, and bFGF mRNA and protein levels in

the retina are significantly increased 3 days after retinal detach-

ment (Fig.2A)4). Time-course experiments revealed elevated

TNFα, IL-1β, and MCP-1 levels within 1 hour of retinal de-

tachment and elevated bFGF levels within 24 hours of detach-

ment (Fig.2B)4). Immunohistochemical analysis showed TNFα

and bFGF expression throughout the retina, whereas IL-1β ex-

pression and MCP-1 expression was localized specifically to as-

trocytes and Muller cells, respectively. These observations indi-

cate that, in addition to monocytes that invade the subretinal space

after retinal detachment, both astrocytes and Muller cells may

be the source of cytokines in vitreous samples from retinal de-

tachment patients. This also suggests that glial cells and mono-

cytes play an important role in the pathogenesis associated with

retinal detachment.

The role of MCP-1 in retinal detachment-induced photoreceptor apoptosis　We previously demonstrated that subretinal administration of

MCP-1, but not IL-1β and TNFα, caused photoreceptor toxic-

ity 24 hours after retinal detachment4). Moreover, MCP-1 admin-

istration caused a significant increase in the number of mono-

cytes in the OPL and subretinal space. Double immunostaining

for MCP-1 and CD11b, a macrophage/microglia marker, clearly

showed that MCP-1 and CD11b colocalize to monocytes in the

OPL (Fig.3). Interestingly, the detached retinas of MCP-1－

deficient mice displayed less retinal detachment-induced photo-

receptor apoptosis and fewer recruited monocytes5). Furthermore,

treatment with an anti-MCP-1 antibody also suppressed photo-

receptor apoptosis in normal mice with detached retinas5). Our

data showed that increased MCP-1 expression in Muller cells

after retinal detachment was responsible for monocyte recruit-

ment to the detached retina.

　Next, we investigated whether MCP-1 induced photoreceptor

apoptosis directly or indirectly through recruited monocytes.

Generally, neuronal MCP-1 expression is very low in the CNS;

however, once an injury occurs, MCP-1-mediated chemoattraction

becomes activated, causing immune cells such as monocytes to

infiltrate the injured region26,27). Recruitment occurs through

MCP-1 binding to the CCR2 receptor, a seven transmembrane G

protein-coupled receptor28). CCR2 was initially thought to be

expressed on immune cells, such as macrophages and activated

lymphocytes29). However, growing evidence suggests that neu-

rons30), glial cells30), and endothelium in the CNS31,32) also express

CCR2, which is upregulated under pathological conditions33).

Fig.3 MCP-1 localizes to macrophages/microglia indetached retina

Immunofluorescence image of detached retina doubleimmunostained with antibodies against MCP-1 (red) and themacrophage/microglia marker CD11b (green) 72 hours afterretinal detachment. Signal for MCP-1 is detected in the cellbody in Muller cells especially in the INL and OPL. The num-ber of CD11b-positive macrophage/microglia is increased inthe OPL. Arrows indicate the co-localization of MCP-1- andCD11b-positive macrophages/microglia within the OPL.

Fig.4 The engulfment of apoptotic photo-receptors by macrophages/microglia

Immunofluorescence image of a detached retinatriple stained with the TUNEL method (red), an anti-body against CD11b (green), and DAPI nuclear stain(blue) 72 hours after retinal detachment. The cellbody of a macrophage/microglial cell is located inthe OPL, whereas its processes are in the ONL,where they appear to engulf a TUNEL-positive pho-toreceptor.

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炎症・再生　Vol.23 No.1 2003526

MCP-1 modulates calcium dynamics through CCR2 in cultured

neurons34). In cultured photoreceptors, a calcium ionophore in-

creases intracellular calcium levels, which results in photore-

ceptor death35). However, our recent findings suggest that MCP-

1 has no toxic effects on cultured photoreceptors if resident mi-

croglial cells are eliminated, indicating that MCP-1 cytotoxicity

occurs through resident microglia present among the cultured

photoreceptors5).

The role of recruited monocytes in reti-nal detachment-induced photoreceptorapoptosis　To further confirm the role of macrophages/microglia in reti-

nal detachment-induced photoreceptor apoptosis, we studied

mice with a deficit in macrophage/microglia recruitment. The

β2 integrin Mac-1 (CD11b/CD18) has an established role in

monocyte recruitment in non-ocular peripheral tissues36). Mac-

1-deficient (Mac-1-/-) mice are less susceptible to brain ischemia-

reperfusion injury compared to wild-type mice37). Activated reti-

nal macrophages/microglia express high amounts of Mac-138).

We observed that Mac-1-/- mice mount a significantly reduced

macrophage/microglia response to retinal detachment. Indeed,

these mice display fewer macrophages/microglia in the OPL and

subretinal space. Moreover, these macrophages/microglia show

fewer signs of morphological activation. In contrast to wild-type

mice, Mac-1-/- mice did not show a decrease in ONL thickness or

an increase in the number of TUNEL-positive photoreceptors5),

suggesting an important role for Mac-1-mediated infiltration and

activation of macrophages/microglia during RD-induced photo-

receptor damage.

　Macrophages/microglia have recently been reported to pro-

mote apoptosis of developing Purkinje cells by engulfing and

terminating apoptotic cells that produce superoxide ions39,40).

Similar events are often observed in detached retinas (Fig.4).

Generally, oxidative stress is one of the major cytotoxic factors

contributing to photoreceptor death in various pathological

conditions41,42). Consistent with these findings are our recent re-

sults showing that oxidative stress mediates MCP-1 cytotoxicity

both in vitro and in vivo5). Suppression of macrophages/micro-

glia or antioxidant treatment may thus represent alternative

neuroprotection strategies against photoreceptor apoptosis.

Conclusions　In the present review, we describe a glia-leukocyte network

regulated by Muller cell-derived MCP-1 and discuss how inhi-

bition of MCP-1 can prevent retinal detachment-induced photo-

receptor apoptosis (Fig.5). Activated macrophages and micro-

glia are toxic to detached photoreceptors, in part due to oxidative

stress, a key toxic factor affecting photoreceptors. Anti-inflam-

matory and antioxidant therapy and direct inhibition of MCP-1

represent new strategies for treating many retinal diseases asso-

ciated with retinal detachment-induced photoreceptor apoptosis.

In our review, we answered, in part, two key questions relating

to the mechanisms underlying retinal detachment-induced pho-

toreceptor apoptosis: (1) Is monocyte recruitment to apoptotic

photoreceptors mediated by a chemoattractant system? (2) Are

recruited monocytes toxic to photoreceptors? Further studies are

needed to clarify the early events that occur during Muller cell

activation and whether other cytokines, such as TNFα and IL-1β,

enhance the effects of MCP-1 signaling on photoreceptor

apoptosis.

Acknowledgements　This work was supported by a grant-in-aid for scientific research fromthe Ministry of Education, Science and Culture of the Japanese govern-ment (T.N.19791255); a Bausch & Lomb Vitreoretinal Fellowship (T.N.);

Mini Review　Neuroprotection against photoreceptor apoptosis

Fig.5 Diagram of a glia-leukocyte network show-ing the role of Muller cell-derived MCP-1 inpromoting photoreceptor apoptosis in the de-tached retina

Following retinal detachment, IL-1β, TNFα, and MCP-1 be-come upregulated in retinal glial cells. MCP-1 directs macroph-ages/microglia to invade the OPL. These cells have a cyto-toxic effect on photoreceptors.

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527Inflammation and Regeneration　Vol.28 No.6 NOVEMBER 2008

the Suda Glaucoma Research Foundation (T.N.); and the Uehara Memo-rial Foundation (T.N.). We thank Prof. J. W. Miller (Massachusetts Eyeand Ear Infirmary, Harvard Medical School, Boston, MA) and Prof. L. I.Benowitz (Children's Hospital, Harvard Medical School, Boston, MA) forhelpful discussions and for direction on this project.

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