Purchase this article with an account.
shulong hu, Bertrand Calippe, Sophie Lavalette, José Sahel, Florian Sennlaub, Xavier P Guillonneau; Up-regulation of P2RX7 in Cx3cr1-deficient mononuclear phagocytes leads to increased interleukin-1β secretion and photoreceptor neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):845.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Inflammatory mononuclear phagocytes (MP) accumulate in geographic atrophy form of age related macular degeneration (AMD) which are associated with photoreceptor degeneration. We have previously shown that Cx3cr1-deficient mice develop age-related subretinal accumulation of MP with photoreceptor degeneration. Cx3cr1-deficient MP have been shown to lead to increased neuronal apoptosis through IL-1beta (IL-1β) in the brain. However the mechanisms for this increased IL-1β secretion from Cx3cr1-deficient MP is still unknown.
Bone marrow monocytes (BMM) were isolated from wildtype and Cx3cr1-deficient mice and analyzed by flow cytometry for P2RX7 expression. Equal numbers of wildtype and Cx3cr1-deficient BMM were co-cultured with wildtype retinal explants or purified photoreceptor outer segment (POS). After 18 hours, BMM-derived MP mRNA expression of specific pro- or anti-infammmatory markers were assayed by qPCR. ATP and IL-1β were assayed in BMM-derived supernatants. In specific experiments, TUNEL staining was performed on retinal explants to assay the neurotoxicity of wildtype and Cx3cr1-deficient BMM.
Cx3cr1-deficient BMM have an increased surface expression of P2RX7 and secreted increased amount of IL-1β upon TLR stimulation in an P2RX7-dependent mechanism when compared to wildtype BMM. Culturing Cx3cr1-deficient BMM in the presence of POS enhanced the expression of inflammatory genes such as IL-1β and P2RX7 while in similar conditions wildtype BMM express higher levels of CD206 and IL-1Ra. Cx3cr1-deficient BMM have an increased photoreceptor toxicity in a BMM/retina co-culture model. Addition of IL-1Ra or Brilliant blue G efficiently reduce photoreceptor cell loss in the BMM/retina co-culture.
We here show that spontaneous P2RX7 activation and enhanced IL-1β secretion are responsible for subretinal CX3CR1-deficient MP photoreceptor toxicity. Our results suggest that inhibition of the inflammasome may reduce photoreceptor cell loss in AMD
This PDF is available to Subscribers Only