We are continuing working on a mouse model of subretinal hemorrhage that we have created to characterize the inflammatory responses and photoreceptor degeneration that occur in the acute aftermath of hemorrhage. It was observed that microglial infiltration into the outer retina commences as early as 6 hours after hemorrhage. Inflammatory cells progressively accumulate in the outer nuclear layer concurrently with photoreceptor degeneration and apoptosis. Administration of minocycline, an inhibitor of microglial activation, decreased microglial expression of chemotactic cytokines in vitro and reduced microglial infiltration and photoreceptor cell loss after subretinal hemorrhage in vivo. Currently, we are employing this model to examine microglial communications with Muller cells, particularly that underlying TSPO-mediated signaling. We found that microglial activation in this model is accompanied by the induced expression of TSPO. The inducibility and effects of TSPO signaling in the retina reveal a mechanism of coordinated macroglia-microglia interactions, the function of which is to limit the magnitude of inflammatory responses after their initiation, facilitating a return to baseline quiescence. Our results indicate that TSPO is a promising molecular marker for imaging inflammatory cell activation in the retina and highlight DBI-TSPO signaling as a potential target for immodulatory therapies

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000505-04
Application #
8938348
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Ma, Wenxin; Wong, Wai T (2016) Aging Changes in Retinal Microglia and their Relevance to Age-related Retinal Disease. Adv Exp Med Biol 854:73-8
Zabel, Matthew K; Zhao, Lian; Zhang, Yikui et al. (2016) Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1-CX3CR1 signaling in a mouse model of retinitis pigmentosa. Glia 64:1479-91
Indaram, Maanasa; Ma, Wenxin; Zhao, Lian et al. (2015) 7-Ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration. Sci Rep 5:9144
Karlstetter, Marcus; Scholz, Rebecca; Rutar, Matt et al. (2015) Retinal microglia: just bystander or target for therapy? Prog Retin Eye Res 45:30-57
Wang, Minhua; Wang, Xu; Zhao, Lian et al. (2014) Macroglia-microglia interactions via TSPO signaling regulates microglial activation in the mouse retina. J Neurosci 34:3793-806
Wong, Wai T (2013) Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Front Cell Neurosci 7:22
Cukras, Catherine A; Petrou, Philip; Chew, Emily Y et al. (2012) Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study. Invest Ophthalmol Vis Sci 53:3865-74
Roger, Jerome E; Ranganath, Keerthi; Zhao, Lian et al. (2012) Preservation of cone photoreceptors after a rapid yet transient degeneration and remodeling in cone-only Nrl-/- mouse retina. J Neurosci 32:528-41
Zhao, Lian; Ma, Wenxin; Fariss, Robert N et al. (2011) Minocycline attenuates photoreceptor degeneration in a mouse model of subretinal hemorrhage microglial: inhibition as a potential therapeutic strategy. Am J Pathol 179:1265-77