Control of Innate Inflammatory Responses in the Retina
Co-Principal InvestigatorsSteve Abcouwer, PhD Regents of the University of Michigan
The presence of low-grade inflammation over long periods of time is one aspect of the damage to the retina that occurs in age-related macular degeneration (AMD), a disease responsible for visual handicap in millions of elderly people. Specialized cells in the retina express a class of cell-surface proteins that are known to play a role in opposing inflammatory responses in other tissues of the body. The purpose of our proposed studies is to determine the role of these proteins in decreasing inflammatory responses in the retina. The outcome of this research will lead to increased understanding of the mechanism responsible for controlling inflammation in the retina, and the possibilities for developing novel therapies aimed at regulating this mechanism.
The goal of our studies is to understand the regulation of inflammatory responses that contribute to the development of age-related macular degeneration (AMD). We are studying specialized cells in the retina that express a class of surface proteins known to play a role in opposing inflammatory responses in other tissues of the body. Our interest lies in determining whether these same proteins play a role in decreasing inflammatory responses in the retina, and the possibilities for developing novel therapies aimed at regulating such mechanisms.
Chronic inflammation is associated with multiple diseases that have their onset in late life. In AMD, chronic inflammation contributes to cumulative damage leading to the death and dysfunction of the light-sensing photoreceptor cells and the supporting retinal pigment epithelium (RPE). The innate immune system plays a central role in triggering inflammatory responses in the retina. The RPE and retinal microglia, the two main classes of phagocytic cells in the retina, express surface proteins that are also found in immune cells and have the potential to either increase or decrease inflammation. Retinal microglia serve as monitors of tissue health and integrity. In response to photoreceptor damage, activated microglia migrate to the outer retina, where they can cause a pronounced inflammatory response. We are studying whether mechanisms in immune cells which normally hold this response in check also act to blunt inflammatory responses in the retina; in addition, we plan to evaluate a means for externally regulating this mechanism.
Our research will be performed using primary cell cultures of RPE and retinal microglia derived from normal and phagocytosis-defective rats. The studies aim to determine which activating molecules and conditions are most effective in opposing pro-inflammatory responses in the retina; whether the surface proteins of interest upregulate suppressors of inflammation through interactions with inhibitory proteins; and whether inhibiting mechanisms that downregulate this mechanism can upregulate internal protective responses in the retina.
This investigation of mechanisms which hold the potential to enhance the anti-inflammatory capacity of the phagocytic cells of the retina addresses a critical need. Currently we lack understanding of the control of inflammatory responses in the retina. The outcomes of our studies are predicted to have significant impact. The results will provide new insights into the regulation of inflammation and cell survival in the retina, and may point out possibilities for new approaches to the treatment of AMD and other retinal conditions associated with chronic inflammation.