NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components

Doyle, Sarah; Campbell, Matthew; Ozaki, Ema; Salomon, Robert G.; Mori, Andres; Kenna, Paul F.; Farrar, G. Jane; Kiang, Anna‐Sophia; Humphries, Marian M.; Lavelle, Ed C.; O’Neill, Luke A. J.; Hollyfield, Joe G.; Humphries, Peter

doi:10.1038/nm.2717

Cited by 386 publications

(479 citation statements)

References 50 publications

Supporting

Mentioning

449

Contrasting

Order By: Relevance

“…The consequence is a switch to a more 'classical' chronic inflammatory responses propagating tissue destruction and angiogenesis and as 'frame-shots' of evidence in man supports. 3,[85][86][87] The cause of change from parainflammation to chronic inflammation remains unknown. We can however make inroads and unwrap possible mechanisms for AMD by comparing with immunemediated uveitis and the role of innate immunity and, in particular, macrophages.…”

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

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

show abstract

“…Similar to T2DM and Alzheimer's disease, drusen consists of amyloid beta, a pro-inflammatory molecule that also activates complement [142] and the NLRP3 inflammasome [130,132]. Drusen components, complement C1q and oxidized lipids, activate the NLRP3 inflammasome resulting in increased production of the pro-inflammatory cytokines, IL-1 and IL-18 [156]. IL-18 is thought to protect against AMD by inhibiting VEGF and thus preventing the pathological neovascularization in wet AMD.…”

Section: Pdmentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

View full text Add to dashboard Cite

Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

show abstract

“…94,95 Interestingly, a recent study has shown that isolated drusen harvested from AMD eyes have the ability to activate the inflammasome in bone marrow-derived macrophages with the release of both IL-18 and IL-1. 96 IL-18 has further been shown to promote RPE cell damage and atrophy (akin to dry AMD) 97 while there is also evidence that the IL-18 may be anti-angiogenic 96 and thus protective for wet AMD. It is intriguing to consider the possibility that the local secretion and tissue concentration of a single cytokine may determine the outcome and type of AMD and thus bear directly on visual prognosis (dry vs wet vs no AMD).…”

Section: Pathology Of Macular Degenerationmentioning

confidence: 99%