TY - JOUR
T1 - Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death
AU - Kataoka, K.
AU - Matsumoto, H.
AU - Kaneko, H.
AU - Notomi, S.
AU - Takeuchi, K.
AU - Sweigard, J. H.
AU - Atik, A.
AU - Murakami, Y.
AU - Connor, K. M.
AU - Terasaki, H.
AU - Miller, J. W.
AU - Vavvas, D. G.
N1 - Funding Information:
Acknowledgements. We thank Tetsu Asami, MD, PhD, Takeshi Iwase, MD, PhD, and Yasuki Ito, MD, PhD, for their assistance in the collection of patients’ samples. We also thank Wendy Chao, PhD for her support in critical review. This work was supported by: NEI R21EY023079-01A1 (DGV); The Yeatts Family Foundation (DGV, JWM); The Loefflers Family Fund (DGV, JWM); the 2013 Macula Society Research Grant award (DGV); Bausch & Lomb Vitreoretinal Fellowship (HM); a Physician Scientist Award (DGV), an unrestricted grant (JWM) from the Research to Prevent Blindness Foundation; NIH R01EY022084–01/S1 (KMC), and NEI grant EY014104 (MEEI Core Grant).
Publisher Copyright:
© 2015 Macmillan Publishers Limited All rights reserved.
PY - 2015/4/23
Y1 - 2015/4/23
N2 - Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal cell death. Moreover, the cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1β, an end product of inflammasome activation. In an animal model of RD, photoreceptor cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying photoreceptors. Inflammasome inhibition attenuated photoreceptor death after RD. Our data implicate the infiltrating macrophages as a source of damaging inflammasomes after photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases.
AB - Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal cell death. Moreover, the cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1β, an end product of inflammasome activation. In an animal model of RD, photoreceptor cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying photoreceptors. Inflammasome inhibition attenuated photoreceptor death after RD. Our data implicate the infiltrating macrophages as a source of damaging inflammasomes after photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases.
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U2 - 10.1038/cddis.2015.73
DO - 10.1038/cddis.2015.73
M3 - Article
C2 - 25906154
AN - SCOPUS:84989899970
SN - 2041-4889
VL - 6
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 4
M1 - e1731
ER -
