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Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration.

ABSTRACT: There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I : C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3(-/-) mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I : C)-induced retinal degeneration. Moreover, after poly(I : C) injection, Rip3(-/-) mice displayed decreased levels of pro-inflammatory cytokines (such as TNF-α and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I : C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF-α and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF-α and IL-6 production after poly(I : C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.

SUBMITTER: Murakami Y

PROVIDER: S-EPMC3890945 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Inflammation, necrosis, and the kinase RIP3 are key mediators of AAG-dependent alkylation-induced retinal degeneration.

Project description:DNA-alkylating agents are commonly used to kill cancer cells, but the base excision repair (BER) pathway they trigger can also produce toxic intermediates that cause tissue damage, such as retinal degeneration (RD). Apoptosis, a process of programmed cell death, is assumed to be the main mechanism of this alkylation-induced photoreceptor (PR) cell death in RD. Here, we studied the involvement of necroptosis (another programmed cell death process) and inflammation in alkylation-induced RD. Male mice exposed to a methylating agent exhibited a reduced number of PR cell rows, active gliosis, and cytokine induction and macrophage infiltration in the retina. Dying PRs exhibited a necrotic morphology, increased 8-hydroxyguanosine abundance (an oxidative damage marker), and overexpression of the necroptosis-associated genes Rip1 and Rip3 The activity of PARP1, which mediates BER, cell death, and inflammation, was increased in PR cells and associated with the release of proinflammatory chemokine HMGB1 from PR nuclei. Mice lacking the anti-inflammatory cytokine IL-10 exhibited more severe RD, whereas deficiency of RIP3 (also known as RIPK3) conferred partial protection. Female mice were partially protected from alkylation-induced RD, showing reduced necroptosis and inflammation compared to males. PRs in mice lacking the BER-initiating DNA glycosylase AAG did not exhibit alkylation-induced necroptosis or inflammation. Our findings show that AAG-initiated BER at alkylated DNA bases induces sex-dependent RD primarily by triggering necroptosis and activating an inflammatory response that amplifies the original damage and, furthermore, reveal new potential targets to prevent this side effect of chemotherapy.

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c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis.

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Programmed necrosis and apoptosis differentially regulate cancer development and biliary homeostasis in the liver

Project description:For years, the term apoptosis was used synonymously for programmed cell death. However, it was recently discovered that programmed necrosis M-bM-^@M-^S dependent on the kinases Receptor-Interacting-Protein-Kinase (RIP)1 and RIP3 (also called necroptosis) M-bM-^@M-^S represents a major programmed cell-death pathway in development and immunity. At present, the functions of necroptosis in hepatitis, liver cancer development and biliary disease are unclear. Here we show that in mice with chronic hepatitis due to conditional ablation of TGF-beta-activated kinase1 (TAK1) in liver parenchymal cells (LPC), both apoptotic and necroptotic signaling pathways are activated. Strikingly, only Caspase-8-dependent apoptosis promotes spontaneous liver cancer development, while in contrast LPC necroptosis inhibits hepatic tumourigenesis. The tumour-promoting effect of apoptosis results from an induction of strong compensatory proliferation of LPC, linked with the paracrine action of growth factors like Insulin-like growth factor-2 (IGF-2) not induced by necroptosis. In addition to prevention of HCC development, induction of necroptosis leads to massive cholestasis and hyperbilirubinemia, resulting from an insufficient ductular reaction and biliary regeneration from the hepatic stem cell niche as a response to chronic hepatitis. These results indicate previously undefined distinctive functions of apoptosis and programmed necrosis in controlling cancer development and cholestasis in the liver with important implications for future therapeutic strategies in chronic liver disease. 8 samples were analysed. We compared groups of 4 Tak1/Caspase8 LPC double knockout mice and 4 Tak1 LPC-KO/Rip3-/- mice to detect genes differentially regulated by apoptotic and necrotic signalling pathways.

2013-04-01 | E-GEOD-39750 | biostudies-arrayexpress

IGF-1, Inflammation and Retinal Degeneration: A Close Network.

Project description:Retinal degenerative diseases are a group of heterogeneous diseases that include age-related macular degeneration (AMD), retinitis pigmentosa (RP), and diabetic retinopathy (DR). The progressive degeneration of the retinal neurons results in a severe deterioration of the visual function. Neuroinflammation is an early hallmark of many neurodegenerative disorders of the retina including AMD, RP and DR. Microglial cells, key components of the retinal immune defense system, are activated in retinal degenerative diseases. In the microglia the interplay between the proinflammatory/classically activated or antiinflammatory/alternatively activated phenotypes is a complex dynamic process that occurs during the course of disease due to the different environmental signals related to pathophysiological conditions. In this regard, an adequate transition from the proinflammatory to the anti-inflammatory response is necessary to counteract retinal neurodegeneration and its subsequent damage that leads to the loss of visual function. Insulin like-growth factor-1 (IGF-1) has been considered as a pleiotropic factor in the retina under health or disease conditions and several effects of IGF-1 in retinal immune modulation have been described. In this review, we provide recent insights of inflammation as a common feature of retinal diseases (AMD, RP and RD) highlighting the role of microglia, exosomes and IGF-1 in this process.

| S-EPMC6041402 | biostudies-literature

Programmed necrosis and apoptosis differentially regulate cancer development and biliary homeostasis in the liver

Project description:For years, the term apoptosis was used synonymously for programmed cell death. However, it was recently discovered that programmed necrosis – dependent on the kinases Receptor-Interacting-Protein-Kinase (RIP)1 and RIP3 (also called necroptosis) – represents a major programmed cell-death pathway in development and immunity. At present, the functions of necroptosis in hepatitis, liver cancer development and biliary disease are unclear. Here we show that in mice with chronic hepatitis due to conditional ablation of TGF-beta-activated kinase1 (TAK1) in liver parenchymal cells (LPC), both apoptotic and necroptotic signaling pathways are activated. Strikingly, only Caspase-8-dependent apoptosis promotes spontaneous liver cancer development, while in contrast LPC necroptosis inhibits hepatic tumourigenesis. The tumour-promoting effect of apoptosis results from an induction of strong compensatory proliferation of LPC, linked with the paracrine action of growth factors like Insulin-like growth factor-2 (IGF-2) not induced by necroptosis. In addition to prevention of HCC development, induction of necroptosis leads to massive cholestasis and hyperbilirubinemia, resulting from an insufficient ductular reaction and biliary regeneration from the hepatic stem cell niche as a response to chronic hepatitis. These results indicate previously undefined distinctive functions of apoptosis and programmed necrosis in controlling cancer development and cholestasis in the liver with important implications for future therapeutic strategies in chronic liver disease.

2013-04-01 | GSE39750 | GEO

Concurrent acute retinal necrosis and orbital inflammation: Report of 2 cases.

Project description:PurposeTo describe the rare entity of concurrent herpetic acute retinal necrosis (ARN) and orbital inflammation.ObservationsTwo cases of ARN with simultaneous orbital inflammation are described. A 40-year old male presented with a painful left eye and hand motion visual acuity (VA). Both panuveitis and orbital inflammation with involvement of the sclera and optic nerve were observed. He was initially treated with oral steroid therapy, after which the orbital inflammation improved but the panuveitis remained. A diagnostic anterior chamber paracentesis was positive for HSV-2 by PCR. He was started on systemic antivirals, but ultimately developed a retinal detachment. The second patient was an 18-year old female with hand motion VA in the left eye. Panuveitis and severe conjunctival chemosis were observed. MRI demonstrated dacryoadenitis with preseptal inflammation. The patient was initially started on oral steroid therapy, which alleviated the orbital inflammation but not the intraocular inflammation. An anterior chamber diagnostic paracentesis was positive for HSV-1, after which the patient underwent vitrectomy for a retinal detachment. The patient was started on systemic antiviral therapy.Conclusions and importanceHerpetic disease should remain on the differential for cases of concurrent intraocular and orbital inflammation. Early recognition of this process may help prevent severe vision loss. It is important to recognize that orbital inflammation secondary to herpetic disease may be diverse in its presentation.

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Project description:Although extensively investigated in inflammatory conditions, the role of pro-inflammatory microRNAs (miRNAs), miR-155 and miR-146a, has not been well-studied in retinal degenerative diseases. We therefore aimed to explore the role and regulation of these miRNA in the degenerating retina, with a focus on miR-155. C57BL/6J mice were subjected to photo-oxidative damage for up to 5 days to induce focal retinal degeneration. MiR-155 expression was quantified by qRT-PCR in whole retina, serum, and small-medium extracellular vesicles (s-mEVs), and a PrimeFlow™ assay was used to identify localisation of miR-155 in retinal cells. Constitutive miR-155 knockout (KO) mice and miR-155 and miR-146a inhibitors were utilised to determine the role of these miRNA in the degenerating retina. Electroretinography was employed as a measure of retinal function, while histological quantification of TUNEL+ and IBA1+ positive cells was used to quantify photoreceptor cell death and infiltrating immune cells, respectively. Upregulation of miR-155 was detected in retinal tissue, serum and s-mEVs in response to photo-oxidative damage, localising to the nucleus of a subset of retinal ganglion cells and glial cells and in the cytoplasm of photoreceptors. Inhibition of miR-155 showed increased function from negative controls and a less pathological pattern of IBA1+ cell localisation and morphology at 5 days photo-oxidative damage. While neither dim-reared nor damaged miR-155 KO animals showed retinal histological difference from controls, following photo-oxidative damage, miR-155 KO mice showed increased a-wave relative to controls. We therefore consider miR-155 to be associated with the inflammatory response of the retina in response to photoreceptor-specific degeneration.

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MicroRNAs in Intervertebral Disc Degeneration, Apoptosis, Inflammation, and Mechanobiology.

Project description:Intervertebral disc (IVD) degeneration is a multifactorial pathological process associated with low back pain, the leading cause of years lived in disability worldwide. Key characteristics of the pathological changes connected with degenerative disc disease (DDD) are the degradation of the extracellular matrix (ECM), apoptosis and senescence, as well as inflammation. The impact of nonphysiological mechanical stresses on IVD degeneration and inflammation, the mechanisms of mechanotransduction, and the role of mechanosensitive miRNAs are of increasing interest. As post-transcriptional regulators, miRNAs are known to affect the expression of 30% of proteincoding genes and numerous intracellular processes. The dysregulation of miRNAs is therefore associated with various pathologies, including degenerative diseases such as DDD. This review aims to give an overview of the current status of miRNA research in degenerative disc pathology, with a special focus on the involvement of miRNAs in ECM degradation, apoptosis, and inflammation, as well as mechanobiology.

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Systemic Injection of RPE65-Programmed Bone Marrow-Derived Cells Prevents Progression of Chronic Retinal Degeneration.

Project description:Bone marrow stem and progenitor cells can differentiate into a range of non-hematopoietic cell types, including retinal pigment epithelium (RPE)-like cells. In this study, we programmed bone marrow-derived cells (BMDCs) ex vivo by inserting a stable RPE65 transgene using a lentiviral vector. We tested the efficacy of systemically administered RPE65-programmed BMDCs to prevent visual loss in the superoxide dismutase 2 knockdown (Sod2 KD) mouse model of age-related macular degeneration. Here, we present evidence that these RPE65-programmed BMDCs are recruited to the subretinal space, where they repopulate the RPE layer, preserve the photoreceptor layer, retain the thickness of the neural retina, reduce lipofuscin granule formation, and suppress microgliosis. Importantly, electroretinography and optokinetic response tests confirmed that visual function was significantly improved. Mice treated with non-modified BMDCs or BMDCs pre-programmed with LacZ did not exhibit significant improvement in visual deficit. RPE65-BMDC administration was most effective in early disease, when visual function and retinal morphology returned to near normal, and less effective in late-stage disease. This experimental paradigm offers a minimally invasive cellular therapy that can be given systemically overcoming the need for invasive ocular surgery and offering the potential to arrest progression in early AMD and other RPE-based diseases.

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