Attenuated adenosine mediated immune-dampening increases natural killer cell activity in early age-related macular degeneration
Archana Padmanabhan NairSayan GhoshVishnu Suresh BabuPraveen MachirajuYing XinGanesh Ram SahuTanuja VaidyaJayasree DebnathKarthick RajaSantosh Gopi Krishna GaddeThirumalesh MBNaren ShettyAtul SaxenaRohit ShettyStacey HoseVrushali DeshpandeKoushik ChakrabarthyJames T. HandaJiang QianSwaminathan SethuDebasish SinhaArkasubhra Ghosh
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Abstract:
Non-exudative age-related macular degeneration (AMD) involves retinal pigment epithelium (RPE) dysfunction and has been linked to altered intraocular immunity. Our investigation focuses on immune cell subsets and inflammation-associated factors in the eyes with early and intermediate AMD. We observed elevated levels of activated natural killer (NK) cells and interferon-γ, concurrent with reduced myeloid-derived suppressor cells (MDSCs) and adenosine in AMD eyes. Aqueous humor from AMD patients had diminished ability to dampen NK cell activation, an effect rescued by adenosine supplementation. The Cryba1 cKO mouse model recapitulated these immune alterations, and single-cell RNA-sequencing identified NK cell-related genes and NK cell-RPE interactions. Co-culture of activated NK cells with RPE cells induced barrier dysfunction and Gasdermin-E driven pyroptosis providing a functional link relevant to AMD. These findings suggest a double-hit model where elevated immune activation and loss of immune dampening mechanisms drive AMD progression. Resetting the intraocular immune balance may be a promising therapeutic strategy for managing early and intermediate AMD.Keywords:
Pyroptosis
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Pyroptosis is a new way of programmed cell death, a number of researches have found that it is associated with a variety of diseases. Inflammasome and caspase protein family play key roles in regulating pyroptosis.Intracellular pattern recognition receptor oligomers under external stimulus, then assemble with apoptotic speck-like protein containing a caspase recruitment domain and caspase precursor into inflammatory complex body, thus activation of caspase can induce pyroptosis. While as the upstream regulation mechanism of pyroptosis, inflammasome might be double edged sword for tumor growth.On the one hand, inflammasome can inhibit the proliferation of tumor cells by inducing pyroptosis; on the other hand, the cumulative effect of the inflammsome can also form a suitable microenvironment for tumor cells and promote tumor growth.
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Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy.
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Pyroptosis is a newly discovered proinflammatory form of programmed cell death. Pyroptosis, which depends on cysteinyl aspartate specific proteinase-1(caspase-1), is inherently the proinflammatory response of the cell.Triggered by various pathological stimuli, pyroptosis is crucial for controlling virus infections.Despite that there are similarities between pyroptosis and necrosis(or apoptosis), there are apparent differences.This review discusses the feature of pyroptosis and the viruses which induce or inhibit pyroptosis.
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The gasdermins (GSDM), a family of pore-forming proteins, consist of gasdermin A (GSDMA), gasdermin B (GSDMB), gasdermin C (GSDMC), gasdermin D (GSDMD), gasdermin E (GSDME) and DFNB59 (Pejvakin (PJVK)) in humans. These proteins play an important role in pyroptosis. Among them, GSDMD is the most extensively studied protein and is identified as the executioner of pyroptosis. Other family members have also been implicated in certain cancers. As a unique form of programmed cell death, pyroptosis is closely related to tumor progression, and the inflammasome, an innate immune mechanism that induces inflammation and pyroptosis. In this review, we explore the current developments of pyroptosis, the inflammasome, and especially we review the gasdermin family members and their role in inducing pyroptosis and the possible therapeutic values in antitumor effects.
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Pyroptosis is a form of regulated cell death that is characterized by gasdermin processing and increased membrane permeability. Caspase-1 and caspase-11 have been considered to be essential for gasdermin D processing associated with inflammasome activation. In the present study, we found that NLRP3 inflammasome activation induces delayed necrotic cell death via ASC in caspase-1/11-deficient macrophages. Furthermore, ASC-mediated caspase-8 activation and subsequent gasdermin E processing are necessary for caspase-1-independent necrotic cell death. We define this necrotic cell death as incomplete pyroptosis because IL-1β release, a key feature of pyroptosis, is absent, whereas IL-1α release is induced. Notably, unprocessed pro-IL-1β forms a molecular complex to be retained inside pyroptotic cells. Moreover, incomplete pyroptosis accompanied by IL-1α release is observed under the pharmacological inhibition of caspase-1 with VX765. These findings suggest that caspase-1 inhibition during NLRP3 inflammasome activation modulates forms of cell death and permits the release of IL-1α from dying cells.
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