Overexpression of S100A4 protects retinal ganglion cells against retinal ischemia-reperfusion injury in mice

Yang, Jiayi; Yang, Ning; Luo, Jinyuan; Cheng, Gumeng; Zhang, Xiao; He, Tao; Xing, Yiqiao

doi:10.1016/j.exer.2020.108281

Cited by 26 publications

(15 citation statements)

References 35 publications

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“…Previous studies have shown that NLRC5 can mediate apoptosis in acute kidney injury, cerebral ischemia/reperfusion injury, and acute myocardial infarction ( Han et al, 2018 ; Liu et al, 2020 ; Yang et al, 2020 ). However, little is known about the function of NLRC5 in the apoptosis pathway during RIR injury.…”

Section: Discussionmentioning

confidence: 99%

The Regulatory NOD-Like Receptor NLRC5 Promotes Ganglion Cell Death in Ischemic Retinopathy by Inducing Microglial Pyroptosis

Deng

Sheng

et al. 2021

Front. Cell Dev. Biol.

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Retinal ischemia is a common pathological event that can result in retinal ganglion cell (RGC) death and irreversible vision loss. The pathogenic mechanisms linking retinal ischemia to RGC loss and visual deficits are uncertain, which has greatly hampered the development of effective treatments. It is increasingly recognized that pyroptosis of microglia contributes to the indirect inflammatory death of RGCs. In this study, we report a regulatory NOD-like receptor, NOD-, LRR- and CARD-containing 5 (NLRC5), as a key regulator on microglial pyroptosis and the retinal ischemia process. Through an in-depth analysis of our recently published transcriptome data, we found that NLRC5 was significantly up-regulated in retina during ischemia–reperfusion injury, which were further confirmed by subsequent detection of mRNA and protein level. We further found that NLRC5 was upregulated in retinal microglia during ischemia, while NLRC5 knockdown significantly ameliorated retinal ischemic damage and RGC death. Mechanistically, we revealed that knockdown of NLRC5 markedly suppressed gasdermin D (GSDMD) cleavage and activation of interleukin-1β (IL-1β) and caspase-3, indicating that NLRC5 promotes both microglial pyroptosis and apoptosis. Notably, we found that NLRC5 directly bound to NLRP3 and NLRC4 in inflammasomes to cooperatively drive microglial pyroptosis and apoptosis mediating retinal ischemic damage. Overall, these findings reveal a previously unidentified key contribution of NLRC5 signaling to microglial pyroptosis under ischemia or hypoxia conditions. This NLRC5-dependent pathway may be a novel therapeutic target for treatment of ischemic retinopathy.

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Section: Discussionmentioning

confidence: 99%

The Regulatory NOD-Like Receptor NLRC5 Promotes Ganglion Cell Death in Ischemic Retinopathy by Inducing Microglial Pyroptosis

Deng

Sheng

et al. 2021

Front. Cell Dev. Biol.

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“…It has been demonstrated that intervention measures that only compete against the mechanisms of in situ RGC death cannot satisfactorily recover the degenerated visual function following RI/R. Regrettably, previous research merely focused on preventing RGCs from death [27,31], while ignoring the transneuronal degeneration following RI/R [32]. Presently, we found that relay cell edema, intracellular mitochondrial proliferation, and the increase in the number of presynaptic vesicles and mitochondria in IPL were emerged in the early stage after RI/R injury (2 hours to 12 hours, RGCs did not appear to be significantly lost).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transneuronal Degeneration in the Visual Pathway of Rats following Acute Retinal Ischemia/Reperfusion

Zhang

et al. 2021

Disease Markers

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The maintenance of visual function not only requires the normal structure and function of neurons but also depends on the effective signal propagation of synapses in visual pathways. Synapses emerge alterations of plasticity in the early stages of neuronal damage and affect signal transmission, which leads to transneuronal degeneration. In the present study, rat model of acute retinal ischemia/reperfusion (RI/R) was established to observe the morphological changes of neuronal soma and synapses in the inner plexiform layer (IPL), outer plexiform layer (OPL), and dorsal lateral geniculate nucleus (dLGN) after retinal injury. We found transneuronal degeneration in the visual pathways following RI/R concretely presented as edema and mitochondrial hyperplasia of neuronal soma in retina, demyelination, and heterotypic protein clusters of axons in LGN. Meanwhile, small immature synapses formed, and there are asynchronous changes between pre- and postsynaptic components in synapses. This evidence demonstrated that transneuronal degeneration exists in RI/R injury, which may be one of the key reasons for the progressive deterioration of visual function after the injury is removed.

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“…In addition, suppression of S100A4 can also reduce the expression of cAMP response element-binding protein (CREB) and B-cell lymphoma-2 (Bcl-2), and increase the expression of caspase-3, to promote apoptosis and prevent abnormal neovascularization [ 118 ]. Interestingly, overexpression of S100A4 provides neuroprotection in ischemic mice by activating the Akt pathway, thus suppressing apoptosis in RGCs [ 104 ]. Damage signals from S100A4 may influence diverse signaling pathways in different retinal cell types to elicit unique responses for protection against ischemia.…”

Section: Damps In Retinal Disordersmentioning

confidence: 99%

Damage-Associated Molecular Patterns (DAMPs) in Retinal Disorders

Mahaling

Low

Beck

et al. 2022

IJMS

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Damage-associated molecular patterns (DAMPs) are endogenous danger molecules released from the extracellular and intracellular space of damaged tissue or dead cells. Recent evidence indicates that DAMPs are associated with the sterile inflammation caused by aging, increased ocular pressure, high glucose, oxidative stress, ischemia, mechanical trauma, stress, or environmental conditions, in retinal diseases. DAMPs activate the innate immune system, suggesting their role to be protective, but may promote pathological inflammation and angiogenesis in response to the chronic insult or injury. DAMPs are recognized by specialized innate immune receptors, such as receptors for advanced glycation end products (RAGE), toll-like receptors (TLRs) and the NOD-like receptor family (NLRs), and purine receptor 7 (P2X7), in systemic diseases. However, studies describing the role of DAMPs in retinal disorders are meager. Here, we extensively reviewed the role of DAMPs in retinal disorders, including endophthalmitis, uveitis, glaucoma, ocular cancer, ischemic retinopathies, diabetic retinopathy, age-related macular degeneration, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, and inherited retinal disorders. Finally, we discussed DAMPs as biomarkers, therapeutic targets, and therapeutic agents for retinal disorders.

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Overexpression of S100A4 protects retinal ganglion cells against retinal ischemia-reperfusion injury in mice

Cited by 26 publications

References 35 publications

The Regulatory NOD-Like Receptor NLRC5 Promotes Ganglion Cell Death in Ischemic Retinopathy by Inducing Microglial Pyroptosis

The Regulatory NOD-Like Receptor NLRC5 Promotes Ganglion Cell Death in Ischemic Retinopathy by Inducing Microglial Pyroptosis

Transneuronal Degeneration in the Visual Pathway of Rats following Acute Retinal Ischemia/Reperfusion

Damage-Associated Molecular Patterns (DAMPs) in Retinal Disorders

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