TLR-Independent and P2X7-Dependent Signaling Mediate<i>Alu</i>RNA-Induced NLRP3 Inflammasome Activation in Geographic Atrophy

Kerur, Nagaraj; Hirano, Yoshio; Tarallo, Valeria; Fowler, Benjamin J.; Bastos-Carvalho, Ana; Yasuma, Tetsuhiro; Yasuma, Reo; Kim, Young‐Hee; Hinton, David R.; Kirschning, Carsten J.; Gelfand, Bradley D.; Ambati, Jayakrishna

doi:10.1167/iovs.13-12500

Cited by 139 publications

(140 citation statements)

References 28 publications

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…Amyloid β, perhaps best known for its suspected role in Alzheimer's disease (Kang et al 1987;Hardy and Higgins 1992;Hardy and Selkoe 2002), was found to be a drusen component in AMD patients (Johnson et al 2002;Dentchev et al 2003). Ocular amyloid deposits in a mouse model of Alzheimer's disease were associated with retinal degeneration (Ning et al 2008) and RPE stress , and amyloid β is known to activate the NLRP3 inflammasome (Halle et al 2008), consistent with other findings that inflammasome activation may mediate GA Kerur et al 2013;Kim et al 2014;Gelfand et al 2015). Based on the studies suggesting amyloid β accumulation may contribute to ocular pathologies in mouse models of AMD Catchpole et al 2013), a clinical trial testing the efficacy of a monoclonal antibody against amyloid β is currently underway (Danis et al 2015).…”

Section: Neuroprotective Agentssupporting

confidence: 79%

“…A series of studies published within the last five years indicate DICER1 reduction in GA patients may contribute to RPE cell death because the enzyme is required to degrade cytotoxic Alu RNA transcripts (Kaneko et al 2011). Increases in Alu RNA transcripts in GA patients cause activation of the NLRP3 inflammasome Dridi et al 2012), ultimately resulting in P2X7-dependent Caspase-8-mediated RPE cell death (Kerur et al 2013;Kim et al 2014). These observations are supported by other data showing this signaling pathway can be instigated by the presence of excess iron (Gelfand et al 2015), which has also been previously associated with AMD in humans (Wong et al 2007).…”

Section: Inflammatory Modulatorsmentioning

confidence: 99%

See 1 more Smart Citation

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Narayanan

Kuppermann

2016

Handbook of Experimental Pharmacology

View full text Add to dashboard Cite

Section: Neuroprotective Agentssupporting

confidence: 79%

Section: Inflammatory Modulatorsmentioning

confidence: 99%

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Narayanan

Kuppermann

2016

Handbook of Experimental Pharmacology

View full text Add to dashboard Cite

“…72 For example, cells from eyes with AMD exhibit upregulated expression of immune receptors and molecules, 73,74 including expression of IL-17RC, a receptor for a dimer of IL-17A and IL-17F and activation of NLRP3 inflammasome, that promotes cleavage of pro-IL-1beta and IL-18. [75][76][77] Furthermore, both macrophages and multinucleated giant cells, mainly associated with vascular channels and breaks in Bruch's membrane are evident. [78][79][80][81][82][83] Macrophage subtype changes have been noted in the eyes of patients with AMD, including a change in the M1/M2 ratio in AMD eyes, compared with that in control eyes of the same age.…”

Section: Understanding Uveitismentioning

confidence: 99%

Doyne lecture 2016: intraocular health and the many faces of inflammation

Dick

2016

Eye

View full text Add to dashboard Cite

Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses.

show abstract

“…For instance, in human cells, endogenous dsRNA formed by pairing of inverted Alu repeats is released from the nucleus during mitosis to activate the dsRNA-binding protein PKR, and repress translation (Kim et al 2014). In a potentially related example, elevated levels of endogenous, repetitive Alu RNA, resulting from Dicer deficiency, leads to noncanonical activation of the NLRP3 inflammasome via MyD88 signaling (Tarallo et al 2012;Kerur et al 2013). Structured elements within mRNAs also serve as important regulatory elements, influencing translatability and stability.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide profiling of the C. elegans dsRNAome

Whipple

Youssef

Aruscavage

et al. 2015

RNA

View full text Add to dashboard Cite

Recent studies hint that endogenous dsRNA plays an unexpected role in cellular signaling. However, a complete understanding of endogenous dsRNA signaling is hindered by an incomplete annotation of dsRNA-producing genes. To identify dsRNAs expressed in Caenorhabditis elegans, we developed a bioinformatics pipeline that identifies dsRNA by detecting clustered RNA editing sites, which are strictly limited to long dsRNA substrates of Adenosine Deaminases that act on RNA (ADAR). We compared two alignment algorithms for mapping both unique and repetitive reads and detected as many as 664 editing-enriched regions (EERs) indicative of dsRNA loci. EERs are visually enriched on the distal arms of autosomes and are predicted to possess strong internal secondary structures as well as sequence complementarity with other EERs, indicative of both intramolecular and intermolecular duplexes. Most EERs were associated with protein-coding genes, with ∼1.7% of all C. elegans mRNAs containing an EER, located primarily in very long introns and in annotated, as well as unannotated, 3 ′ UTRs. In addition to numerous EERs associated with coding genes, we identified a population of prospective noncoding EERs that were distant from protein-coding genes and that had little or no coding potential. Finally, subsets of EERs are differentially expressed during development as well as during starvation and infection with bacterial or fungal pathogens. By combining RNA-seq with freely available bioinformatics tools, our workflow provides an easily accessible approach for the identification of dsRNAs, and more importantly, a catalog of the C. elegans dsRNAome.

show abstract

TLR-Independent and P2X7-Dependent Signaling MediateAluRNA-Induced NLRP3 Inflammasome Activation in Geographic Atrophy

Abstract: NF-κB and P2X7 are critical signaling intermediates in Alu RNA-induced inflammasome priming and RPE degeneration. These molecules are novel targets for rational drug development for geographic atrophy.

Cited by 139 publications

References 28 publications

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Doyne lecture 2016: intraocular health and the many faces of inflammation

Genome-wide profiling of the C. elegans dsRNAome

Contact Info

Product

Resources

About