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As the resident immune cells in the retina, microglia play important homeostatic roles in retinal immune regulation and neuroprotection. However, chronic microglia activation is a common hallmark of many degenerative retinal diseases. The semi-synthetic tetracycline antibiotic, minocycline, appears to inhibit pro-inflammatory microglia which coincides with protection against photoreceptor cell degeneration. A sub-type of microglia termed disease associated microglia (DAM) have recently been associated with a wide range of central nervous system (CNS) diseases. In this study we examine the kinetics of microglia infiltration towards the outer retina of rhodopsin knockout mice (Rho -/- ) by immunofluorescence, and undertake transcriptional and spatial localization analysis of markers for evidence of both homeostatic function and appearance of DAM. We demonstrate in the Rho -/- mice, IBA1 + and P2RY12 + microglia take on an activated morphology early in disease, prior to notable photoreceptor loss and are capable of infiltrating the subretinal space. Expression of lipid processing enzyme and DAM-marker lipoprotein lipase (LPL) is primarily observed only after microglia have traversed the ONL. Administration of minocycline to Rho -/- mice induced loss of phagocytic/DAM microglia in the outer retina in vivo coinciding with photoreceptor survival and amelioration of retinal degeneration. Overall, we show that minocycline suppresses many DAM markers, in particular those associated with lipid metabolism indicating that suppression of this process is one mechanism by which minocycline protects against inflammation induced photoreceptor cell death., (Copyright © 2022. Published by Elsevier Ltd.)

Retinal degeneration is the leading cause of incurable blindness worldwide and is characterised by progressive loss of light-sensing photoreceptors in the neural retina. SARM1 is known for its role in axonal degeneration, but a role for SARM1 in photoreceptor cell degeneration has not been reported. SARM1 is known to mediate neuronal cell degeneration through depletion of essential metabolite NAD and induction of energy crisis. Here, we demonstrate that SARM1 is expressed in photoreceptors, and using retinal tissue explant, we confirm that activation of SARM1 causes destruction of NAD pools in the photoreceptor layer. Through generation of rho -/- sarm1 -/- double knockout mice, we demonstrate that genetic deletion of SARM1 promotes both rod and cone photoreceptor cell survival in the rhodopsin knockout ( rho -/- ) mouse model of photoreceptor degeneration. Finally, we demonstrate that SARM1 deficiency preserves cone visual function in the surviving photoreceptors when assayed by electroretinography. Overall, our data indicate that endogenous SARM1 has the capacity to consume NAD in photoreceptor cells and identifies a previously unappreciated role for SARM1-dependent cell death in photoreceptor cell degeneration., (© 2020 Ozaki et al.)

Retinal degeneration is a form of neurodegenerative disease and is the leading cause of vision loss globally. The Toll-like receptors (TLRs) are primary components of the innate immune system involved in signal transduction. Here we show that TLR2 induces complement factors C3 and CFB, the common and rate-limiting factors of the alternative pathway in both retinal pigment epithelial (RPE) cells and mononuclear phagocytes. Neutralization of TLR2 reduces opsonizing fragments of C3 in the outer retina and protects photoreceptor neurons from oxidative stress-induced degeneration. TLR2 deficiency also preserves tight junction expression and promotes RPE resistance to fragmentation. Finally, oxidative stress-induced formation of the terminal complement membrane attack complex and Iba1+ cell infiltration are strikingly inhibited in the TLR2-deficient retina. Our data directly implicate TLR2 as a mediator of retinal degeneration in response to oxidative stress and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide and while polymorphisms in genes associated with the immune system have been identified as risk factors for disease development, the underlying pathways and mechanisms involved in disease progression have remained unclear. In AMD, localised inflammatory responses related to particulate matter accumulation and subsequent "sterile" inflammation has recently gained considerable interest amongst basic researchers and clinicians alike. Typically, inflammatory responses in the human body are caused as a result of bacterial or viral infection, however in chronic conditions such as AMD, extracellular particulate matter such as drusen can be "sensed" by the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, culminating in the release of the two pro-inflammatory cytokines IL-1β and IL-18 in the delicate local tissue of the retina. Identification at the molecular level of mediators of the inflammatory response in AMD may yield novel therapeutic approaches to this common and often severe form of blindness. Here, we will describe the role of IL-18 in AMD and other forms of retinal disorders. We will outline some of the key functions of IL-18 as it pertains to maintaining tissue homeostasis in a healthy and degenerating/diseased retina.

This correction notice addresses errors in a scientific article titled "Caspase-1-dependent inflammasomes mediate photoreceptor cell death in photo-oxidative damage-induced retinal degeneration." The errors involve the use of the same group of wildtype mice as a comparison to multiple knockout models in several figures. The corrected information shows that Caspase1/11−/− mice have better-preserved retinal function and reduced inflammation and cell death following photo-oxidative damage compared to wildtype controls. Similarly, Nlrp3−/− mice show better-preservation of retinal function following photo-oxidative damage compared to wildtype controls. On the other hand, Casp11−/− mice show no preservation of retinal function following photo-oxidative damage. The correction also addresses errors in the legends of Supplementary Figures 1, 2, and 3, clarifying that the wildtype controls used in these figures are the same as in other figures. [Extracted from the article]

The metallome has been involved in the pathological investigation into ocular tissue for decades; however, as technologies advance, more information can be ascertained from individual tissue sections that were not previously possible. Herein, a demonstration of complementary techniques has been utilized to describe the distribution and concentrations of essential metals in both wildtype (WT) and rhodopsin (Rho−/−) ocular tissues. The multimodal approach described is an example of complementary datasets that can be produced when employing a multifaceted analytical approach. Heterogenous distributions of copper and zinc were observable within both WT and Rho−/− tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), and the distributions of further trace elements notoriously problematic for ICP-MS analysis (phosphorous, Sulfur, chlorine, potassium, calcium, iron, and aluminum) were analysed by particle-induced X-ray emission (PIXE). [ABSTRACT FROM AUTHOR]

SARM1 (sterile alpha and armadillo motif-containing protein) is a highly conserved Toll/IL-1 Receptor (TIR) adaptor with important roles in mediating immune responses. Studies in the brain have shown that SARM1 plays a role in induction of neuronal axon degeneration in response to a variety of injuries. We recently demonstrated that SARM1 is pro-degenerative in a genetic model of inherited retinopathy. This current study aimed to characterise the effect of SARM1 deletion in an alternative model of retinal degeneration (RD) in which the retinal pigment epithelium (RPE) fragments following administration of oxidising agent, sodium iodate (NaIO3), leading to subsequent photoreceptor cell death. Following administration of NaIO3, we observed no apparent difference in rate of loss of RPE integrity in SARM1 deficient mice compared to WT counterparts. However, despite no differences in RPE degeneration, photoreceptor cell number and retinal thickness were increased in Sarm1–/– mice compared to WT counterparts. This apparent protection of the photoreceptors in SARM1 deficient mice is supported by an observed decrease in pro-apoptotic caspase-3 in the photoreceptor layer of Sarm1–/– mice compared to WT. Together these data indicate a pro-degenerative role for SARM1 in the photoreceptors, but not in the RPE, in an oxidative stress induced model of retinal degeneration consistent with its known degenerative role in neurons in a range of neurodegenerative settings. [ABSTRACT FROM AUTHOR]

Activation of the inflammasome is involved in the progression of retinal degenerative diseases, in particular, in the pathogenesis of Age-Related Macular Degeneration (AMD), with NLRP3 activation the focus of many investigations. In this study, we used genetic and pharmacological approaches to explore the role of the inflammasome in a mouse model of retinal degeneration. We identify that Casp1/11−/− mice have better-preserved retinal function, reduced inflammation and increased photoreceptor survivability. While Nlrp3−/− mice display some level of preservation of retinal function compared to controls, pharmacological inhibition of NLRP3 did not protect against photoreceptor cell death. Further, Aim2−/−, Nlrc4−/−, Asc−/−, and Casp11−/− mice show no substantial retinal protection. We propose that CASP-1-associated photoreceptor cell death occurs largely independently of NLRP3 and other established inflammasome sensor proteins, or that inhibition of a single sensor is not sufficient to repress the inflammatory cascade. Therapeutic targeting of CASP-1 may offer a more promising avenue to delay the progression of retinal degenerations. [ABSTRACT FROM AUTHOR]

Neovascularization is a hallmark pathology of numerous retinal diseases from diabetic retinopathy (DR) to age-related related macular degeneration (AMD). Over the past 2 decades, the rise of anti-VEGF based medications for neovascular eye conditions has revolutionized the treatment paradigm for patients and preserved the vision of millions. With any form of therapy however, there remain pitfalls and areas for improved interventions. Here, we succinctly present some current views on treatment options for patients with retinal and choroidal neovascularization. We also highlight some of the most promising therapeutic strategies currently being developed and where these therapies may fit with the current clinical standard of care. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. While activation of the immune system has been implicated in disease progression, the pathways involved remain relatively unclear. Typically, inflammatory responses are caused as a result of pathogenic infection. However, in chronic conditions, like AMD, a form of 'sterile' inflammation can exist in localised areas of the body in response to modified host-derived elements and particulate matter accumulation, due to the activation of a complex termed the 'inflammasome'. Inflammasomes control the activity of two major pro-inflammatory cytokines, namely, interleukin (IL)-1β and IL-18, by allowing for their cleavage from inactive pro-forms into mature cytokines. The major pathological hallmark common to both 'dry' and 'wet' AMD is the presence of extracellular deposits, known as drusen, below the retinal pigment epithelium in the macula of the eye. Past studies have shown that host-derived particulate matter such as amyloid deposits and atherosclerotic plaques can be 'sensed' by the NLRP3-inflammasome causing cleavage of pro-IL-1β and pro-IL-18. We have recently reported that the NLRP3-inflammasome can also 'sense' drusen isolated from human AMD donor eyes and that IL-18 protects against the development of choroidal neovascularisation in a model that mimics 'wet' AMD. In fact, since then, a number of studies have reported roles for the NLRP3-inflammasome in AMD. This review will focus on describing, comparing and contrasting these reports and analyzing the potential for manipulating the NLRP3-inflammasome as a therapy for AMD. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Drusen accumulation is the major pathological hallmark common to both dry and wet AMD. Although activation of the immune system has been implicated in disease progression, the pathways involved are unclear. Here we show that drusen isolated from donor AMD eyes activates the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, causing secretion of interleukin-1? (IL-1?) and IL-18. Drusen component C1Q also activates the NLRP3 inflammasome. Moreover, the oxidative-stress-related protein-modification carboxyethylpyrrole (CEP), a biomarker of AMD, primes the inflammasome. We found cleaved caspase-1 and NLRP3 in activated macrophages in the retinas of mice immunized with CEP-adducted mouse serum albumin, modeling a dry-AMD-like pathology. We show that laser-induced choroidal neovascularization (CNV), a mouse model of wet AMD, is exacerbated in Nlrp3?/? but not Il1r1?/? mice, directly implicating IL-18 in the regulation of CNV development. These findings indicate a protective role for NLRP3 and IL-18 in the progression of AMD. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that the pro-inflammatory cytokine IL-18 may have utility as an anti-angiogenic agent in the eye. Numerous laboratories, including our own have demonstrated the ability of murine IL-18 to prevent neovascularization in the retina, choroid and cornea in pathological scenarios. Here, we summarize the potential use of IL-18 as an immunotherapy for wet age-related macular degeneration treatment, describing past and recent findings pertaining to its biological function in the eye. [ABSTRACT FROM AUTHOR]

A response from the authors of an article related to therapeutic use of interleukin-18 (IL-18) for neovascular age-related macular degeneration, published in the periodical "Science Translational Medicine" in 2014, is presented.