Unit on Neuron-Glia Interactions in Retinal Disease

Individual photo of Dr. Wong.
Wai T. Wong

Wai T. Wong, M.D., Ph.D.
(301) 496-1758
wongw@nei.nih.gov

Research Interests

The mission of our unit (UNGIRD) is to explore and understand the fundamental biological mechanisms underlying retinal diseases and translate these findings into proof-of-concept clinical studies to discover new therapies. We have the following starting point: that discovering the interactions between the cellular (neuronal and glia) components of the retina and elucidating how these may be pathological altered are central to the understanding and management of retinal disease. Because many retinal diseases such as diabetic retinopathy, retinal vein occlusions, age-related macular degeneration, involve a key inflammatory component, UNGIRD has focused on the study of the resident immune cell in the retina, the microglial cell, and how it interacts with other retinal cells in the healthy and diseased retina.

Our unit operates at 3 levels with a central focus on retinal microglia:

  1. Basic scientific study of the retina, addressing the cellular mechanisms in the healthy retina: Basic study of the microglia cell in the retina, involving its morphology, physiology, and cellular interactions with other retinal cell types
  2. Translational study of the retina in disease models: Preclinical study of the involvement of retinal microglia in the aging retina, and in models of retinal disease
  3. Clinical study of retinal diseases and its manifestations: Clinical study of the inflammatory involvement in common retinal diseases, including the targeting inflammation and microglial activation as a therapeutic strategy in proof-of-concept Phase I/II clinical trials.

Our key areas of work are:

  1. Understanding the basic physiology of microglia in the retina:

    Retinal microglia share many similarities with those found elsewhere in the CNS, but however, possess some distinguishing features in their morphology, distribution, and neighboring cells types that may relate to specialized functions. Unlike in the brain, ramified retinal microglia are arrayed in the inner retina in non-overlapping horizontal mosaic arrays with their processes are concentrated in the inner and outer plexiform layers in close proximity to retinal synapses. Interestingly, the outer retina, where photoreceptors and the retinal pigment epithelium (RPE) are located, is normally devoid of microglia coverage. Additionally, microglia are in proximity to, and interact with, specialized retinal cells types, such as Müller cells and RPE cells. We are interested in understanding the interactions that retinal microglia have with these specialized retinal cells in the endogenous functioning of the retina.

    Building on our prior work that provided the initial characterization of dynamic microglial behavior and injury response in the retina, we have continued to elucidate the interactions that microglia have with retina neurons and Müller cells to understand the place that microglia have in the retina. We determined that microglia are constitutively responding to neuronal communications in the retina in the form of neurotransmission, and that microglial dynamic activity is regulated as a function of overall neuronal activity within the retina (Fontainhas et al., PLoS One, 2011). With regards to interactions with Müller cells, we established that microglia, through activation, are able to induce marked changes in Müller cell morphology, physiology, and gene expression in ways that are suited to mediating adaptive responses within the retina following injury (Wang et al., J. Neuroinflammation, 2011). We have also characterized a molecular mode of microglia-Müller cell interaction in the retina via DBI-TSPO signaling whose function may be to limit the magnitude of inflammatory responses following injury/inflammation and to facilitate a return to baseline quiescence in establishing homeostasis (Wang et al., J. Neuroscience, 2014).

  2. To understand how microglia undergo change in the aging retina and how this contributes to age-related retinal disease:

    As common retinal diseases have a strong age-related association, we initiated this project to discover whether and how microglia undergo change in the aging retina and how these changes can contribute to age-related retinal disease. This theme has been identified by the NEI Audacious Goal (AG) Initiative as a High Priority Area of Research: “Intersection of Aging and Biological Mechanisms of Eye Disease”. In recent work, we have established that retinal microglia do indeed undergo significant senescent change in the aging retina in terms of their morphology, distribution, behavior, and responses to injury in ways that suggest a constitutive loss of surveillance function, and a more dysregulated and less reversible response to injury (Damani et al., Aging Cell, 2011). The age-related migration of microglia to the subretinal space also results in their accumulation of intracellular lipofuscin and A2E increases their activation state and dysregulates their expression of complement regulatory proteins. This results in increased inflammation and complement activation in the RPE-Bruch’s membrane interface in ways related to those implicated in AMD pathogenesis (Ma et al., Neurobiology of Aging, 2013a). Intrinsically, we found through microarray gene profiling experiments that patterns of gene expression in retinal microglia change progressively with aging, involving pathways subserving microglial immune function and regulation, angiogenesis, trophic factors, and complement and complement regulatory proteins, suggesting possible mechanisms related to neuroinflammation and neurodegeneration in the retina (Ma et al., Neurobiology of Aging, 2013b). We have recently summarized our ideas and concepts on microglia aging in a review article entitled, “Microglial Aging in the Healthy CNS: Phenotypes, Drivers, and Rejuvenation” (Wong, Front Cell Neurosci. 2013).

  3. To understand how microglia are altered in retinal disease, how they may drive disease progression, and how they can be inhibited in preclinical experiments and in clinical trials:

    In exploring the role of microglia in retinal degeneration and AMD and possible microglia-directed interventions, we examined microglial involvement in a murine model of subretinal hemorrhage in hemorrhagic neovascular AMD. We found that microglia activation and its related inflammatory responses in subretinal hemorrhage can drive photoreceptor loss, and that microglial inhibition with minocycline may contribute to the treatment of exudative AMD complicated by subretinal hemorrhage (Zhao et al., Am. Journal of Pathology, 2011). We also completed an initial proof-of-concept Phase II clinical trial for microglial inhibition in retinal disease involving the use of oral minocycline for the treatment of diabetic macular edema that illustrated promising initiation results (Cukras et al., IOVS, 2012) and provided important information for future clinical studies in this direction.

Staff

Name Title E-mail
Wai T. Wong, M.D., Ph.D.
PubMed Author Search
Unit Chief wongw@nei.nih.gov
Wenxin Ma, M.D., Ph.D. Scientist (Contractor) mawenxin@nei.nih.gov
Lian Zhao, Ph.D. Scientist (Contractor) zhaolia@mail.nih.gov
Xu Wang, M.D., Ph.D. Scientist (Contractor) xu.wang@nih.gov
Matthew Zabel, Ph.D. Postdoctoral Researcher matthew.zabel@nih.gov
Yikui Zhang, M.D. Postdoctoral Researcher yikui.zhang@nih.gov

Selected Publications

Basic/Translational Studies

  • Indaram M‡, Ma W‡, Zhao L, Fariss RN, Rodriguez IR, Wong WT. 7-Ketocholesterol Increases Retinal Microglial Migration, Activation, and Angiogenicity: A Potential Pathogenic Mechanism Underlying Age-related Macular Degeneration. Scientific Reports, 2015, 5:9144. (‡ indicates equal contribution).
  • Wang, M, Wang, X, Zhao, L, Ma, W, Rodriguez, IR, Fariss, RN, Wong, WT. Macroglia-Microglia Interactions via TSPO Signaling Regulates Microglial Activation in the Mouse Retina. Journal of Neuroscience, 2014, 34:3793-3806.
  • Kumar, A., Zhao, L., Fariss, R.N., McMenamin, P.G., Wong, W.T. Vascular associations and dynamic process motility in perivascular myeloid cells of the mouse choroid: implications for function and senescent change. Investigative Ophthalmology and Visual Science, 2014, 55:1787-96.
  • Wong, W.T. Microglial Aging in the Healthy CNS: Phenotypes, Drivers, and Rejuvenation. Frontiers in Cellular Neuroscience, 2013, 7:22.
  • Ma, W., Cojocaru, R., Gotoh, N., Gieser, L., Villasmil, R., Cogliati, T., Swaroop, A., Wong, W.T. Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation. Neurobiology of Aging, 2013, 34:2310-21.
  • Condren, A.B., Kumar, A., Mettu, P., Liang, K.J., Zhao, L., Tsai, J-Y., Fariss, R.N., Wong, W.T. Perivascular mural cells of the mouse choroid demonstrate morphological diversity that is correlated with vasoregulatory function. PLoS One, 2013;8(1):e53386.
  • Ma, W., Coon, S., Zhao, L., Fariss, R.N., Wong, W.T. A2E accumulation influences retinal microglial activation and complement regulation. Neurobiology of Aging, 2013, 34(3):943-60.
  • Wang, M., Ma, W., Zhao, L., Fariss, R.N., Wong, W.T. Adaptive Muller Cell Responses to Microglial Activation Mediate Neuroprotection and Coordinate Inflammation in the Retina. Journal of Neuroinflammation, 2011; 8:173.
  • Zhao, L, Ma, W.X., Fariss, R.N., Wong, W.T. Minocycline attenuates photoreceptor degeneration in a mouse model of subretinal hemorrhage: microglial inhibition as a potential therapeutic strategy. American Journal of Pathology, 2011; 179:1265-77.
  • Damani, M., Zhao, L., Fontainhas, A.M., Amaral, J., Fariss, R.N., Wong, W.T. Age-related Alterations in the Dynamic Behavior of Microglia. Aging Cell, 2011;10:263-76.
  • Wong, W.T., Wang, M., Li, W. Regulation of Microglia by Ionotropic Glutamatergic and GABAergic Neurotransmission. Neuron Glia Biology, 2011; 14:1-6.

Clinical Studies

  • Petrou PA, Cunningham D, Shimel K, Harrington M, Hammel K, Cukras CA, Ferris FL, Chew EY, Wong WT. Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial. Invest Ophthalmol Vis Sci. 2014, 56:330-8
  • Toy, B.C., Krishnadev, N., Indaram, M., Cunningham, D., Cukras, C.A., Chew, E.Y., Wong, W.T. Drusen regression is associated with local changes in fundus autofluorescence in intermediate age-related macular degeneration. American Journal of Ophthalmology, 2013;156:532-542
  • Wong, W.T., Dresner, S., Forooghian, F., Glaser, T., Doss, L., Zhou, M., Cunningham, D., Shimel, K., Harrington, M., Hammel, K., Cukras, C.A., Ferris, F.L., Chew, E.Y. Treatment of Geographic Atrophy with Subconjunctival Sirolimus: Results of a Phase I/II Clinical Trial. Investigative Ophthalmology and Visual Science, 2013, 54:2941-50.
  • Meleth, A.D., Toy, B.C., Nigam, D., Agron, E., Chew, E.Y., Wong, W.T. Prevalence and Progression of Pigment Clumping Associated with Idiopathic Macular Telangiectasia Type 2 (IMT2). Retina, 2013, 33:762-70.
  • Toy, B.C., Agrón, E., Nigam, D., Chew, E.Y., Wong, W.T. Longitudinal Analysis of Retinal Hemangioblastomatosis and Visual Function in Ocular von Hippel-Lindau Disease. Ophthalmology, 2012, 119(12):2622-30.
  • Cukras, C.A., Petrou, P., Chew, E.Y., Meyerle, C.B., Wong, W.T. Oral Minocycline for the Treatment of Diabetic Macular Edema (DME): Results of a Phase I/II Clinical Study. Investigative Ophthalmology and Visual Science, 2012, 22: 3865-74.
  • Meleth, A.D., Mettu, P., Agron, E., Chew, E.Y., Sadda, S.R., Ferris, F.L., Wong, W.T. Changes in Retinal Sensitivity in Geographic Atrophy Progression as Measured by Microperimetry. Investigative Ophthalmology and Visual Science, 2011;52:1119-26.
  • Forooghian, F., Chew, E.Y., Meyerle, C.B., Cukras, C., Wong, W.T. Investigation of the Role of Neutralizing Antibodies Against Bevacizumab as Mediators of Tachyphylaxis. Acta Ophthalmologica, 2011; 89:e206-7.
  • Wong, W.T., Kam, W, Cunningham D., Harrington, M., Hammel, K., Meyerle, C.B., Cukras, C., Chew, E.Y., Sadda, S.R., Ferris, F.L. Treatment of Geographic Atrophy by the Topical Administration of OT-551: Results of a Phase II Clinical Trial. Investigative Ophthalmology and Visual Science, 2010; 51:6131-9.
Last Reviewed: 
March 2015