Abstract
BackgroundPhotoreceptor degeneration is a main hallmark of many blinding diseases making protection of photoreceptors crucial to prevent vision loss. Thus, regulation of endogenous neuroprotective factors may be key for cell survival and attenuation of disease progression. Important neuroprotective factors in the retina include H2O2 generated by injured photoreceptors, and leukemia inhibitory factor (LIF) expressed in Müller glia cells in response to photoreceptor damage.ResultsWe present evidence that H2O2 connects to the LIF response by inducing stabilization of Lif transcripts in Müller cells. This process was independent of active gene transcription and p38 MAPK, but relied on AU-rich elements (AREs), which we identified within the highly conserved Lif 3′UTR. Affinity purification combined with quantitative mass spectrometry identified several proteins that bound to these AREs. Among those, interleukin enhancer binding factor 3 (ILF3) was confirmed to participate in the redox-dependent Lif mRNA stabilization. Additionally we show that KH-type splicing regulatory protein (KHSRP) was crucial for maintaining basal Lif expression levels in non-stressed Müller cells.ConclusionsOur results suggest that H2O2-induced redox signaling increases Lif transcript levels through ILF3 mediated mRNA stabilization. Generation of H2O2 by injured photoreceptors may thus enhance stability of Lif mRNA and therefore augment neuroprotective LIF signaling during degenerative conditions in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0137-1) contains supplementary material, which is available to authorized users.
Highlights
Photoreceptor degeneration is a main hallmark of many blinding diseases making protection of photoreceptors crucial to prevent vision loss
H2O2 stabilizes Lif mRNA in Müller glia cells Signaling between degenerating photoreceptors and Müller glia cells induces expression of several neuroprotective factors for photoreceptor survival [2,13,14,15]
Recent evidence suggests that redox mechanisms may be involved in this intercellular communication, and it was proposed that H2O2, which is produced by stressed photoreceptors, might be a molecule responsible for the induction of retinal survival pathways [22,23,24]
Summary
Photoreceptor degeneration is a main hallmark of many blinding diseases making protection of photoreceptors crucial to prevent vision loss. Lif is expressed in a small and dispersed subpopulation of Müller glial cells in response to photoreceptor injury [2] and signals through the LIFR/gp130 receptor complex activating the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway [2,3,12,13]. Activation of this pathway leads to increased expression of endothelin-2 (Edn2), Fgf, Stat, Jak, suppressor of cytokine signaling 3 (Socs3) and glial fibrillary acidic protein, (Gfap) [2,12]
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