Purchase this article with an account.
Kelly Mulfaul, Ema Ozaki, Kiva Brennan, Matthew Campbell, Sarah Doyle; Investigating a role for Toll like receptor signaling in the pathogenesis of Age Related Macular Degeneration (AMD).. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5010.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
One of the biological signatures observed in AMD is the marked deposition sub-retinal pigment epithelium (RPE) of complement factor 3 (C3). Neither the reason nor the outcome of C3 deposition is fully understood. We hypothesize that sterile danger associated molecular patterns (DAMPs) found in the degenerating retina activate Toll like receptor (TLR) signaling pathways to induce C3 expression.
Murine bone marrow derived macrophages, human monocytes and human RPE cells were treated with various TLR ligands over time and assayed by qPCR and Western Blot for C3 expression and secretion.
C3 expression is significantly upregulated in response to TLR2, 3, 4, 7, 8 and 9 ligation in macrophages and TLR2, 3 and 4 ligation in the RPE. C3 is increased at the level of gene expression in response to TLR activation. Furthermore TLR activation results in an increase of C3 secretion from RPE cells and human monocytes. Expression of C3 is regulated by TIR adapter proteins Mal/TIRAP, MyD88 and TRIF.
Despite the complement cascade and TLRs both being critical components of the innate immune response little is known about the interaction between these two pathways. We have demonstrated that TLR activation can promote the expression and secretion of C3, the key complement factor in all three complement cascades. Given the array of possible TLR ligands available in the environment of the degenerating RPE/retina, it is possible that the sheer volume of secretion in response to TLR activation promotes C3 deposition potentially compromising the integrity of the RPE outer blood-retina barrier (oBRB).
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
This PDF is available to Subscribers Only