Dataset Information

Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death.

ABSTRACT: 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-1?, 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.

SUBMITTER: Kataoka K

PROVIDER: S-EPMC4650542 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death.

Kataoka K K Matsumoto H H Kaneko H H Notomi S S Takeuchi K K Sweigard J H JH Atik A A Murakami Y Y Connor K M KM Terasaki H H Miller J W JW Vavvas D G DG

Cell death & disease 20150423

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 inflammasome ...[more]

PMID: 25906154

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Project description:Retinal detachment (RD) occurs in several major retinal conditions and often causes irreversible vision loss due to photoreceptor cell death. Retinal residential microglial cells are activated following RD and participate in photoreceptor cell death via direct phagocytosis and the regulation of inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor exclusively expressed on microglial cells in the retina, and has been reported to affect microglial cell homeostasis, phagocytosis and inflammatory responses in the brain. In this study, increased expression of multiple cytokines and chemokines in the neural retina was observed starting at 3 h following RD. Trem2 knockout (Trem2-/-) mice exhibited significantly more photoreceptor cell death than wild-type controls at 3 days after RD, and the number of TUNEL positive photoreceptor cells progressively decreased from day 3 to day 7 post-RD. A significant thinning of the outer nuclear layer (ONL), with multiple folds was observed in the Trem2-/- mice at 3 days post-RD. Trem2 deficiency reduced microglial cell infiltration and phagocytosis of stressed photoreceptors. There were more neutrophils in Trem2-/- retina following RD than in controls. Using purified microglial cells, we found Trem2 knockout is associated with increased CXCL12 expression. The aggravated photoreceptor cell death was largely reversed by blocking the CXCL12-CXCR4 mediated chemotaxis in Trem2-/- mice after RD. Our findings suggested that retinal microglia are protective in preventing further photoreceptor cell death following RD by phagocytosing presumably stressed photoreceptor cells and by regulating inflammatory responses. TREM2 is largely responsible for such protective effect and CXCL12 plays an important role in regulating neutrophil infiltration after RD. Collectively, our study pinpointed TREM2 as a potential target of microglial cells to ameliorate RD-induced photoreceptor cell death.

Dataset Information

Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death.

Publications

Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death.

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