RT Journal Article
SR Electronic
T1 Upregulation of P2RX7 in <em>Cx3cr1</em>-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6987
OP 6996
DO 10.1523/JNEUROSCI.3955-14.2015
VO 35
IS 18
A1 Shulong J. Hu
A1 Bertrand Calippe
A1 Sophie Lavalette
A1 Christophe Roubeix
A1 Fadoua Montassar
A1 Michael Housset
A1 Olivier Levy
A1 Cecile Delarasse
A1 Michel Paques
A1 José-Alain Sahel
A1 Florian Sennlaub
A1 Xavier Guillonneau
YR 2015
UL http://www.jneurosci.org/content/35/18/6987.abstract
AB Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1-deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1β secretion from Cx3cr1-deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1-deficient mice, has not been elucidated. Here we show that Cx3cr1-deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1β inhibition efficiently blunted Cx3cr1-MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in light-induced subretinal inflammation of Cx3cr1-deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists.