A new study shows that the complement system, part of the innate immune system, plays a protective role to slow retinal degeneration in a mouse model of retinitis pigmentosa, an inherited eye disease. This discovery contradicts previous studies of other eye diseases suggesting that the complement system worsens retinal degeneration. In previous studies, activation of the complement system, which mediates some aspects of inflammation, worsens damage in age-related macular degeneration (AMD)
Researchers monitored the genetic expression of the complement system in a transgenic mouse model of retinitis pigmentosa. They found that upregulation of complement expression and activation coincided with the onset of photoreceptor degeneration. What’s more, this upregulation occurs in the exact location of the degeneration.
Using the retinitis pigmentosa mouse model, the researchers examined the role of proteins C3 and CR3, the central component of complement and its receptor, by comparing mice with genetically ablated C3 or CR3 to mice with normal expression. They found that the absence of C3 or CR3 made degeneration worse. Rod photoreceptors, the light-sensing cells that die off first in retinitis pigmentosa, were precipitously lost along with a surge in the expression of neurotoxic inflammatory cytokines.
They pieced together that C3 gets secreted by microglia, trash-collecting cells that in a healthy retina clear away dead cells by phagocytosis to keep the tissue working properly. Once secreted, C3 lands on dead photoreceptors labeling them for destruction and removal. The receptor, CR3, recognizes the C3 markers and conveys the information to microglia. “Breakdown of this C3-CR3 interaction results in a decreased ability of microglia to phagocytose dead photoreceptors, which then accumulate in the retina, stimulating greater inflammation and degeneration,” said the study’s principal investigator Wai T Wong, M.D., Ph.D., chief the Neuron-Glia Interactions in Retinal Disease Section at NEI. “Degeneration accelerates pretty quickly.”
When placed alongside each other in a dish, microglia from C3- or CR3-ablated retinas turned out to be toxic to photoreceptors. Taken together, the results show that in the context of retinitis pigmentosa, complement activation is actually helpful for clearing away dead cells and maintaining a state of homeostasis, a physiological balance, in the retina.
However, in the context of AMD, harmful effects observed from complement activation have spurred clinical trials testing complement inhibitors. “Our findings suggest that this approach may be appropriate for some disease scenarios, but may induce complex responses in other disease scenarios by inhibiting helpful and homeostatic functions of inflammation,” Dr. Wong said.
Further research is needed to complete the picture of how, and under what circumstances, complement activation has beneficial or harmful effects on photoreceptors and disease progression.
News source: https://www.nei.nih.gov/content/immune-system-can-slow-degenerative-eye-disease-nih-led-mouse-study-shows
Source: National Eye Institute