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Originally published online as doi:10.1189/jlb.1102535 on May 22, 2003

Published online before print May 22, 2003
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(Journal of Leukocyte Biology. 2003;74:161-166.)
© 2003 by Society for Leukocyte Biology

Control of myeloid activity during retinal inflammation

Andrew D. Dick*, Debra Carter*, Morag Robertson{dagger}, Cathryn Broderick{ddagger}, Edward Hughes*, John V. Forrester{dagger} and Janet Liversidge{dagger}

* Division of Ophthalmology, University of Bristol, United Kingdom;
{dagger} Department of Ophthalmology, University of Aberdeen, United Kingdom; and
{ddagger} Institute of Ophthalmology, University College London, United Kingdom

Correspondence: Professor Andrew D. Dick, Division of Ophthalmology, University of Bristol, Bristol Eye Hospital, Lower Maudlin Street, Bristol BS1 2LX, UK. E-mail: a.dick{at}Bristol.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE RETINAL ENVIRONMENT AND...
 MACROPHAGE ACTIVITY DURING...
 CONTROL OF MACROPHAGE ACTIVITY...
 CONCLUDING REMARKS
 REFERENCES
 
Combating myeloid cell-mediated destruction of the retina during inflammation or neurodegeneration is dependent on the integrity of homeostatic mechanisms within the tissue that may suppress T cell activation and their subsequent cytokine responses, modulate infiltrating macrophage activation, and facilitate healthy tissue repair. Success is dependent on response of the resident myeloid-cell populations [microglia (MG)] to activation signals, commonly cytokines, and the control of infiltrating macrophage activation during inflammation, both of which appear highly programmed in normal and inflamed retina. The evidence that tissue CD200 constitutively provides down-regulatory signals to myeloid-derived cells via cognate CD200-CD200 receptor (R) interaction supports inherent tissue control of myeloid cell activation. In the retina, there is extensive neuronal and endothelial expression of CD200. Retinal MG in CD200 knockout mice display normal morphology but unlike the wild-type mice, are present in increased numbers and express nitric oxide synthase 2, a macrophage activation marker, inferring that loss of CD200 or absent CD200R ligation results in "classical" activation of myeloid cells. Thus, when mice lack CD200, they show increased susceptibility to and accelerated onset of tissue-specific autoimmunity.

Key Words: macrophages • microglia • CD200 • sialoadhesin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE RETINAL ENVIRONMENT AND...
 MACROPHAGE ACTIVITY DURING...
 CONTROL OF MACROPHAGE ACTIVITY...
 CONCLUDING REMARKS
 REFERENCES
 
Intraocular inflammation is relatively uncommon yet remains a leading cause of blindness within the working-age population in developed countries [1 , 2 ]. The eye and in particular the retina are regarded as immune-privileged sites providing the environment for cellular and molecular mechanisms that suppress inflammatory responses, while maintaining tissue homeostasis and ultimately securing their vital function. An archetypal example is that of anterior chamber-associated immune deviation, where antigen delivered into the anterior segment of the eye results in systemic down-regulation of systemic immunity, particularly delayed-type hypersensitivity (DTH), to that antigen on subsequent systemic exposure [3 ]. Mechanisms of suppression are numerous and are in part reliant on an intact oculo-splenic axis and ocular FasL expression [4 5 6 7 ]. Increasingly, it is appreciated that the retina, like the anterior chamber of the eye, has active, immune regulatory networks [8 , 9 ], which in combination with the blood retinal barrier, protects against danger signals. Despite the recognized immune privilege, within the eye, there are dendritic cells (DCs) [10 ], but they are notably absent from normal retina. However, early in retinal inflammation, DCs have been described that infiltrate the perivascular space within the glial limitans [11 ], similar to the recent findings in the central nervous system (CNS) [12 ], so that a concept that the initiation of CNS and retinal inflammation is in part facilitated by recruitment of peripheral DC can be drawn. Whether CNS or retina has resident cells that can confer antigen-presenting cell (APC) ability remains controversial. There are two distinct populations of myeloid-derived cells in the retina: perivascular cells (PVCs) and microglia (MG) [13 , 14 ], where their role as APC, immune effectors, or immunomodulators remains unconfirmed. Unlike the CNS [15 ], in the retina, the majority of the myeloid cell population is MG (Fig. 1 ) [16 ]. One inference is that the resident MG, like their CNS counterparts, are pivotal to restricting and regulating immune responses [17 ]. Given that when intraocular inflammation affecting the retina occurs clinically, it is frequently chronic and results in marked tissue destruction, and questions arise as to how regulatory networks are overcome and why there is a relative inability to restore tissue homeostasis.



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  		Figure 1. In human retina, MG constitute the majority of the CD45+ population and are largely major histocompatibility complex (MHC) class II-negative [13 ]. (A) Silver-enhanced staining of CD45+ parenchymal MG in human retina. (B) Confocal images of PVCs expressing MHC class II (fluorescein isothiocyanate) in human retina [counterstained with actin (red) and 4',6-diamidino-2-phenylindole dihydrochloride (blue)].

 
The retina, like the brain, constitutes an environment that interacts with the immune system and can regulate local immune responses. Previously, it has been suggested that CNS pathologies result in part as a result of failure of normal CNS mechanisms [17 ]. These for example include a balance that exists between astrocytes and MG, which serves on the one hand to suppress MG-mediated T helper cell type 1 (Th1) responses and conversely, to regulate tissue damage via astrocyte-mediated (nerve growth factor) suppression of demyelination and possible concomitant suppression of Th2 responses. Similarities of cell-cell interaction to maintain homeostasis exist within retina. Recently, photoreceptor survival during retinal degeneration has been linked with the ability for MG activation to stimulate neurones (in the retina, Muller cells), to secrete growth factors (such as basic fibroblast growth factor), and to maintain photoreceptor survival [18 , 19 ]. There appear in the CNS and the retina tight cellular interactions as well environmental conditions that govern the continued viability and function of neuronal tissue. With respect to leukocytes that are resident with such tissue, although many soluble factors such as macrophage-colony stimulating factor (M-CSF), granulocyte M-CSF, and various cytokines [20 ] play a major role in the regulation and modification of myeloid cell function, to date, relatively few surface-receptor factors have been identified for this role. Leukocyte function, including macrophages, may be regulated by the integration of activation and inhibitory signals received through cell-surface receptors [21 ]. In common with most of the inhibitory receptors is the conservation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic domains, although inhibitory molecules such as cytotoxic T-lymphocyte antigen-4 lack this motif. Targeted disruption of such molecules leads to an increase in autoimmune disorders, which are frequently fatal [22 ]. A paradigm has emerged where the strength of the opposing, activating, and inhibitory signals determine the initiation, amplification, and termination of immune responses [23 ]. This review will present an overview of the environmental conditions and cognate cellular interactions that provide regulation of local immune responses and maintenance of tissue/neuronal integrity, first alluding to the role of the retinal microenvironment and cognate interactions that control resident MG and the influence and control of infiltrating macrophages by the retina during inflammation.


   THE RETINAL ENVIRONMENT AND MG
TOP
 ABSTRACT
 INTRODUCTION
 THE RETINAL ENVIRONMENT AND...
MACROPHAGE ACTIVITY DURING...
 CONTROL OF MACROPHAGE ACTIVITY...
 CONCLUDING REMARKS
 REFERENCES
 
MG are derived from myeloid cell lineage. Macrophages isolated from different tissues and anatomical sites are heterogeneous, and it has long been recognized that resident macrophages are adapted to the local microenvironment [24 , 25 ]. Observations from development studies [26 ], depletion studies [27 ], and differentiation show that the tissue regulates macrophage function [28 ]. Injury leads to a rapid increase in the number of macrophages in an inflamed tissue, and these cells adapt to the local microenvironment by development of a coordinated set of properties that enable them to perform a particular function. Programming is arguably determined by the first cytokine to which macrophages are exposed, from which an essential component of the program is the development of unresponsiveness to other activating cytokines [20 ]. Glomerular macrophages for instance are uncommitted and can be prevented from responding to interferon-{gamma} (IFN-{gamma}) when pretreated with transforming growth factor-ß (TGF-ß) in vivo [29 30 31 ]. The concept of macrophage activation (see review, ref. [32 ]) includes the ability of macrophages to adapt to signals that drive cells into "classical" and "alternative" pathways by IFN-{gamma} or interleukin (IL)-4/IL-13-generating immunity/DTH or repair responses, respectively. Additionally, macrophages may respond to innate signals via Toll-like receptor or deactivating signals via TGF-ß, CD47, CD200 receptor (R), and others. In keeping with many of the recent concepts and paradigms of macrophage activation, in the retina, MG adapt to control neuronal growth and are active phagocytes, clearing dying photoreceptor cells [33 ], whereupon responses to photoreceptor degeneration and retinal injury incur MG migration and accumulation [34 ]. For example, resting MG express low levels of CD45 and costimulatory molecules [15 , 35 ] and possess minimal migration and phagocytic activity in situ, all of which may contribute to immune regulation [36 ] induced by TGF-ß {in turn secreted by the retinal pigment epithelium (RPE) [37 ]} programming of myeloid activity. During circumstances of injury or immune-mediated stress, retinal or CNS MG are "activated", associated with up-regulation of CD45, coaccessory molecules, MHC class II expression, and cytokine secretion; migration; and the ability to phagocytose apoptotic cells. To dissect myeloid cell behavior further, we developed a retinal explant model, from where MG readily migrate and display mannan receptor-mediated phagocytosis [38 ]. There have been many reports on the central role of IL-10 in the maintenance of ocular-immune regulation [39 , 40 ]. In context of normal retina, MG in retinal explants, stimulated with a classical activation cocktail of IFN-{gamma}/lipopolysaccharide (LPS), do not respond like uncommitted macrophages but secrete IL-10, which in turn down-regulates B7 complex and CD40 expression and migration [38 , 41 ] and suppresses production of IL-12 or expression of nitric oxide synthase (NOS)2 or generation of NO. However, given the phenotypic propensity to present antigen, much work in the CNS to date has focused on the MG ability to do so, and success depends on whether functional assays have studied neonatal MG or MG cultures [17 ]. Following isolation of MG and perivascular macrophages, direct ex vivo analysis shows that it is the latter that are able to present antigen and not MG [42 ]. Furthermore, although MG interact with T cells [43 ] and support activated T cell effector responses, they do not support IL-2 production or proliferation, and T cell apoptosis results [42 ]. MG, therefore, unlike perivascular macrophage counterparts, provide novel, regulatory measures to down-regulate immune-mediated responses within the retina and CNS and limit tissue damage. Indeed, one implication is that the ability to phagocytose apoptotic cells may in turn down-regulate MG ability to present antigen, akin to macrophage behavior in general [30 , 31 ], thus limiting prolonged tissue-damaging effects of immune responses during neurodegeneration.

Control of microglial activation in situ in normal retina
Recent investigations of CD200 (OX2), a member of the immunoglobulin (Ig) superfamily, and CD200R have demonstrated that macrophages and granulocytes are restrained from tissue-damaging activation through CD200R signaling [44 45 46 ]. The studies demonstrated that CD200 and CD200R are glycoproteins and that CD200R is confined to myeloid cells, which in turn can be phosphorylated on tyrosine residues. Moreover, earlier experiments showed that a blockade of CD200:CD200R resulted in exacerbation of experimental allergic encephalomyelitis (EAE), which together with data from knockout (KO) mice (see below), strongly support a control of myeloid activity by CD200 [46 ]. CD200KO mice demonstrate an increase in myeloid cell numbers, and aggregates in peripheral lymphoid tissue and resident myeloid cell populations within the CNS phenotypically and morphologically appeared activated [45 ] and elicited an exaggerated MG response upon facial nerve transection. In retina, there is widespread expression of CD200 on glial fibrillary acidic protein neurones and endothelium, and CD200R (in the rat at least) is expressed on MG and up-regulated on activated MG during retinal inflammation [47 ]. Regulation of macrophage function is supported by the following observations in CD200KO mice: significant increase in numbers of myeloid-derived cells within lymphoid organs [48 ], activation of MG to express NOS2 [49 ], accelerated onset of experimental autoimmune uveoretinitis (EAU) [49 ] and experimental autoimmune EAE, and conversion of C57BL/6 mice from resistant to susceptible to collagen-induced arthritis [45 ]. Using a retinal explant model [38 , 41 ], we have further shown with preliminary data that MG migration is facilitated by CD200R ligation via CD200:Fc, while inhibiting the effect of IFN-{gamma}/LPS activity on MG (Fig. 2 ) and preventing classical activation of resident MG. This implies, in addition to control of macrophage activation to express for example NOS2, CD200R also signals MG to migrate. Consequently, the role of CD200 expression on endothelium requires further elucidation as to its effects on circulating myeloid cells. The constitutive down-regulation of CNS and retinal macrophages has important implications on how potential deregulation of the CD200:CD200R axis affects not only the course and the severity of autoimmune inflammation but also generation of and tissue response to neurodegenerative conditions.



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  		Figure 2. Mean number of CD45+-adherent MG migrated from a 5-mm retinal explant over 72 h in culture: CD200R signaling maintains microglial ability to migrate. Using experimental conditions, established retinal explant culture model [38 , 40 ], we observed over 72 h of activation of MG with IFN-{gamma} and LPS that the ability of MG to migrate and generate NO from the explant is inhibited as previously documented [40 ]. Maintaining migration can be achieved with signaling via CD200R by CD200:Fc. Maximal effective concentration of CD200:Fc used was established from a dose response (10–200 ng/ml). Retinal trephines (5 mm) were cultured in glucose-enhanced RPMI on cell-culture insert membranes for up to 72 h with or without additional cytokine stimulus. Results represent repeated experiments to achieve mean ± SEM.

 

   MACROPHAGE ACTIVITY DURING RETINAL DEGENERATION
TOP
 ABSTRACT
 INTRODUCTION
 THE RETINAL ENVIRONMENT AND...
 MACROPHAGE ACTIVITY DURING...
CONTROL OF MACROPHAGE ACTIVITY...
 CONCLUDING REMARKS
 REFERENCES
 
The main studies have concentrated on the control of macrophage activity during inflammation and not neurodegeneration. The rds mouse provides a useful model for human outer retinal dystrophies. The mouse is homozygous for a null mutation in the Prph2 gene that encodes the structural protein peripherin/rds, essential for the formation and maintenance of normal photoreceptor outer segments, and thus, without which, photoreceptor apoptosis results [50 ]. During neurodegeneration in rds mice, MG become activated, proliferate, and express sialoadhesin but not NOS2 and do not generate nitrotyrosine (E. Hughes et al., submitted manuscript). The control of MG activity during neurodenegeration and therefore subsequent MG behavior is largely ill-defined. Recent experiments in the rds mouse showed that the greatest photoreceptor death precedes the height of MG activity by at least 5 days, and although MG proliferated, there was no evidence of NO-mediated oxidative damage. Whether MG are deregulated and exacerbate photoreceptor degeneration or in fact respond to limit tissue damage as a result of their microenvironmental conditioning requires further investigation, particularly in light of the observation that there is marked sialoadhesin expression during the course of degeneration. Sialoadhesin is one of a group of macrophage-restricted cell-surface sialic acid receptor proteins named siglecs [51 , 52 ], which has a high degree of conservation between rodents and humans. Their precise role in macrophage function is yet to be fully clarified, but they are thought to be involved in cell-cell and cell-extracellular matrix (ECM) interactions, and human siglecs have structural similarities to ITIMs, which have a regulatory influence over macrophage activity [53 ]. Although sialoadhesin is not thought to be a phagocytic receptor, its expression may facilitate other phagocytic receptors and increase cell-cell and cell-ECM adhesion. Whether this is also involved in bridging innate and acquired immune responses by binding to CD43-positive T cells [54 ] is an avenue for further investigation during neurodegeneration.


   CONTROL OF MACROPHAGE ACTIVITY DURING INFLAMMATION
TOP
 ABSTRACT
 INTRODUCTION
 THE RETINAL ENVIRONMENT AND...
 MACROPHAGE ACTIVITY DURING...
 CONTROL OF MACROPHAGE ACTIVITY...
CONCLUDING REMARKS
 REFERENCES
 
Macrophages entering an inflamed site are placed in an environment where they are exposed to many different signals. Up until now, this review has focused on evidence that resident macrophages, such as MG, in retina and CNS are maintained so as not to "classically" activate unless overrun by environmental conditions such as injury, degeneration, or overwhelming inflammation. Additionally, there is evidence that trafficking of macrophages occurs in normal CNS tissue, but these cells fail to respond classically to acute inflammatory stimuli [55 ]. Whether during inflammation, the retina maintains a capacity to down-regulate classical activation of infiltrating macrophages or "alternatively" activate macrophages has not previously been defined. Such observations would demonstrate an inherent capacity of the tissue environment to contribute toward neuronal repair and open avenues for developing therapeutic strategies during inflammation. Therefore, using the model EAU, a CD4+ T cell-mediated antigen-specific destruction of the retina [56 57 58 ], we can further dissect the control of myeloid cell activity during inflammation. For full disease expression of EAU, a nonspecific macrophage infiltrate is required [59 , 60 ]. In this set of experiments, resident MG behave as though conditioned with TGF-ß and under the influence of CD200R signaling do not express NOS2 but express ß-glucuronidase [49 , 61 ]. During the evolution, peak, and resolution of EAU, infiltrating macrophages show differential programming. Classical macrophage activation following stimulation with IFN-{gamma} and tumor necrosis factor (TNF) refers to the ability of a macrophage to express NOS2 and generate nitrite, peroxynitrites, and superoxides, which in turn induces lipid peroxidation of cell membranes and cell death. This is observed during the overwhelming inflammatory response of peak-phase EAU [61 ]. Like resident MG, which behave as though TGF-ß primed and are resistant to further cytokine stimulation, the abundant number of macrophages isolated during EAU recovery behaves similarly and does not produce nitrite [41 , 61 ]. In peak EAU, infiltrating myeloid cells under the influence of the pronounced cytokine release from the Th1 T cell infiltrate express NOS2 and nitrotyrosine and constitutively release NO. The destructive role of classically activated macrophages has been further demonstrated in experiments where inhibition of NOS2 suppresses expression of and tissue destruction seen in EAU by preventing peroxynitrite formation by macrophages, thus protecting photoreceptor cells from apoptosis [62 , 63 ]. A similar picture is seen when animals evolving EAU are treated with soluble p55 TNF receptor-IgG fusion protein (sTNFr-Ig) [35 ]. All these sets of experiments have furthered our understanding of macrophage conditioning during EAU, the inherent ability of the retina to control macrophage activation, and in the latter experiments, the mechanisms by which anti-TNF therapies are active during suppression of target organ damage. sTNFr-Ig suppresses clinical EAU and tissue damage without significantly altering the retinal T cell or macrophage infiltrate [35 , 64 ]. Treatment does suppress T cell-derived IFN-{gamma} production [64 ] and macrophage-derived NO production during the height of disease. It is possible that sTNFr-Ig binds and inhibits soluble TNF (solTNF) and membrane TNF (memTNF) on T cells, thus preventing T cell activation and IFN-{gamma} production and subsequent IFN-{gamma}/TNF-mediated activation of infiltrating macrophages during EAU. Generally, however, solTNF is regarded as the ligand for p55 or TNFr1 [65 ]. TNFr1 contains death domains mediating apoptosis upon engagement [66 ] but also under other circumstances, may mediate cell survival [67 ]. Recent evidence strongly infers that memTNF supports the generation of lymphoid structures, and solTNF is required for the generation of full phenotype of inflammatory lesions, as shown in experimental models of autoimmunity within the CNS [68 ]. That sTNFr-Ig treatment delayed but did not impair cell movement into the retina yet did suppress the full phenotype of tissue damage implies in the main that the principal action is against solTNF. If that is the case, then the main action opposes T cell-derived TNF and IFN-{gamma} production, which in turn reduces the ability to activate macrophages when infiltrating the retina. Studies emphasize the distinct roles for macrophages at different stages during the evolution of EAU and the importance of homeostatic control of resident macrophage populations as well as infiltrating macrophage programming in determining which role they adopt. Such regulation permits the down-regulation of macrophage activity and allows, with subsequent redress of the microenvironment during disease course, a new influx of macrophages to be alternatively programmed and provide different functions.


   CONCLUDING REMARKS
TOP
 ABSTRACT
 INTRODUCTION
 THE RETINAL ENVIRONMENT AND...
 MACROPHAGE ACTIVITY DURING...
 CONTROL OF MACROPHAGE ACTIVITY...
 CONCLUDING REMARKS
REFERENCES
 
The retina, similar to the CNS, is empowered with numerous mechanisms to respond to danger effectively, control inflammation, and resume normal function without a debilitating healing response (Fig. 3 ). This requires a fine balance between the control of resident myeloid cell population, principally MG, via cognate interaction of CD200 ligand on endothelium and neurons and its receptor expressed on macrophages. The result is a continual down-regulation of classical macrophage activation to generate NO in response to IFN-{gamma} and TNF-{alpha}, for instance, and a reduction in the capacity to present antigen but to maintain phagocytic activity to presumably allow clearance of apoptotic bodies (photoreceptors) and debris. In support of endothelial CD200 expression facilitating trafficking of cells, we have noted that MG maintain migratory capacity with CD200:Fc. Cytokines also play a major role, and it is the loss of the predominant and constant TGF-ß conditioning of myeloid cells in the steady-state, overridden by the hierarchical Th1 cytokine response that conditions infiltrating macrophages during inflammation, which delivers the full expression of, in particular, the autoimmune response. Nevertheless, CD200 interaction and TGF-ß conditioning rapidly reprogram newly infiltrated cells during resolution, orchestrating tissue repair and the return to the steady-state.



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  		Figure 3. Schematic representation of cytokine and cognate interactions that control myeloid cell activity in retina. Retinal MG and myeloid cell-infiltrate activity is controlled by cytokine milieu and cognate interactions between CD200R cell-surface receptor on myeloid cells and CD200 ligand expression on neurons [41 ]. The overall response is to down-regulate myeloid cell activity and limit tissue damage as a result of immune response and to maintain the ability to clear debris and apoptotic cells, allowing normal function to resume. Resident MG are conditioned by at least two mechanisms: down-regulation/deactivation by CD200R ligation [45 , 49 , 69 ] and TGF-ß conditioning via RPE. These result in a phenotype of resting MG of MHC class IIlowCD86lowCD40low expression and low NO production [38 ]. Following an inflammatory stimulus with LPS or IFN-{gamma} and TNF-{alpha}, resident MG do not generate NO and further down-regulate MHC class II and CD86 and secrete IL-10 [38 , 61 ]. Although with overwhelming, proinflammatory stimuli, infiltrating macrophages will respond classically to generate NO, the retina continues in its attempt to deactivate, as seen during resolution of EAU when the abundant macrophage infiltrate behaves as though TGF-ß conditions and suppresses NO production at the same time tissue repair is evident. To date, there has been no evidence of alternative macrophage activation in the retina.

 


   ACKNOWLEDGEMENTS
 
The work was supported by Iris fund for the Prevention of Blindness, U.K., Guide Dogs for the Blind Association, U.K., National Eye Research Centre, U.K., and the Wellcome Trust.

Received November 8, 2002; revised January 7, 2003; accepted January 10, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 THE RETINAL ENVIRONMENT AND...
 MACROPHAGE ACTIVITY DURING...
 CONTROL OF MACROPHAGE ACTIVITY...
 CONCLUDING REMARKS
 REFERENCES
 

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