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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-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.
Highlights
Receptorinteracting protein 3 (RIP3)-dependent necrotic pathway is critical for the development of various retinal diseases,[5,10,11] and for several systemic diseases such as acute pancreatitis and antiviral immunity.[8,9,12] Under the specific conditions where caspase-8 is inactivated, necrotic stimuli such as tumor necrosis factor α (TNFα), Fas ligand, and Toll-like receptor (TLR) trigger the formation of a complex called the necrosome, containing receptor-interacting protein 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL).[8,9,13,14,15]
We previously demonstrated that Retinal detachment (RD) leads to both caspase-dependent apoptosis and RIP3-dependent necrosis of photoreceptor cells, and that Rip[3] deletion diminishes photoreceptor cell death during RD.[5]
Upregulation of IL-1β in the central nervous system (CNS) after ischemic and traumatic brain injury has been reported in animals.[44,45]
Summary
RD triggers the activation of inflammasomes, which is diminished by Rip[3] deletion. We previously demonstrated that RD leads to both caspase-dependent apoptosis and RIP3-dependent necrosis of photoreceptor cells, and that Rip[3] deletion diminishes photoreceptor cell death during RD.[5]. The sample from the RPE/choroid complex in RD eyes showed an increase in Il1b mRNA, it was not statistically significant These data suggest that IL-1β largely originates from cells migrating into the subretinal space during RD. To assess whether inhibition of cleaved IL-1β in Rip3− / − mice during RD is due to decreased macrophage recruitment to the site of detachment, we analyzed the numbers of infiltrating macrophages labeled with an anti-CD11b antibody in the detached retina, including the ONL and the subretinal space (Figures 4a and b). Similar to YVAD treatment and IL-1β-neutralizing antibody, Nlrp[3] deletion led to a significant but not complete
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