Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death.
Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death.
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DOI：
10.1038/cddis.2015.73
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发表时间：
2015-04-23
影响因子：
9
通讯作者：
Vavvas DG
中科院分区：
文献类型：
--
作者：
Kataoka K;Matsumoto H;Kaneko H;Notomi S;Takeuchi K;Sweigard JH;Atik A;Murakami Y;Connor KM;Terasaki H;Miller JW;Vavvas DG
光感受器从视网膜色素上皮的脱离见于各种视网膜病症中，导致光感受器死亡和随后的视力丧失。细胞死亡导致内源性分子的释放，所述内源性分子激活含有半胱天冬酶-1的分子平台，称为炎性体。据报道，视网膜疾病中的炎性小体激活在某些情况下是保护性的，而在其他情况下是有害的，导致神经元细胞死亡。此外，视网膜疾病中炎性小体的细胞来源尚不清楚。在这里，我们证明了视网膜脱离（RD）导致感光细胞损伤的患者具有增加的裂解IL-1β水平，IL-1β是炎性小体激活的终产物。在RD的动物模型中，感光细胞死亡导致内源性炎性小体的激活，并且这种激活通过Rip 3缺失而减弱。发现Il 1b表达的主要来源是视网膜下间隙中浸润的巨噬细胞，而不是死亡的光感受器。炎性小体抑制减弱RD后的光感受器死亡。我们的数据表明，浸润性巨噬细胞是感光细胞脱离后以RIP 3依赖性方式损害炎性小体的来源，并提出了治疗视网膜疾病的新治疗靶点。
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.