Endoplasmic reticulum stress and oxidative stress contribute to neuronal pyroptosis caused by cerebral venous sinus thrombosis in rats: Involvement of TXNIP/peroxynitrite-NLRP3 inflammasome activation

Ding, Rui; Ou, Weiyang; Chen, Cheng-Wei; Liu, Yaqi; Li, Haiyan; Zhang, Xifang; Chai, Huihui; Ding, Xiaowen; Wang, Qiujing

doi:10.1016/j.neuint.2020.104856

Cited by 30 publications

(31 citation statements)

References 40 publications

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“…For instance, the collage 2A1 (col2A1), aggrecan (ACAN), and SOX9 were highly expressed in NP cells ( Tu et al, 2021 ). Subsequently, six subtypes of NP cells, namely, metabolic homeostatic NP cells [Met NPC, highly expressing MXRA5 and DKK3 ( Li et al, 2017 ; Poveda et al, 2017 )], adhesive NP cells [Adh NPC, highly expressing VCAM1 ( Rafat et al, 2012 )], inflammatory response NP cells (IR NPC, highly expressing MMP3 and ADAMTS5), endoplasmic reticulum stress NP cells [ERS NPC, highly expressing TXNIP and HSPA1B ( Ding et al, 2020 )], fibrocartilagenous NP cells [Fc NPC, highly expressing FGF1 ( Fernández et al, 2010 )], and CD70 + and CD82 + progenitor NP cells (Pro NPC), were identified. As the proportion alterations of 11 cell types in grades II, III and IV are shown in Figure 1C , we can find that the proportion of metabolic homeostatic NP cells (Met NPC, 32.37%) was the highest at the early period (grade II) of disc degeneration, then the proportion of fibrocartilagenous NP cells (Fc NPC) increased at the middle (grade III, 40.64%) and late (grade IV, 31.11%) period of disc.…”

Section: Resultsmentioning

confidence: 99%

Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in the Progression of Human Intervertebral Disc Degeneration

Ling

Liu

Wang

et al. 2022

Front. Cell Dev. Biol.

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Intervertebral disc degeneration (IDD) has been considered as the primary pathological mechanism that underlies low back pain. Understanding the molecular mechanisms underlying human IDD is imperative for making strategies to treat IDD-related diseases. Herein, we report the molecular programs, lineage progression patterns, and paths of cellular communications during the progression of IDD using single-cell RNA sequencing (scRNA-seq) on nucleus pulposus (NP) cells from patients with different grades of IDD undergoing discectomy. New subtypes of cells and cell-type-specific gene signatures of the metabolic homeostatic NP cells (Met NPC), adhesive NP cells (Adh NPC), inflammatory response NP cells (IR NPC), endoplasmic reticulum stress NP cells (ERS NPC), fibrocartilaginous NP cells (Fc NPC), and CD70 and CD82+ progenitor NP cells (Pro NPC) were identified. In the late stage of IDD, the IR NPC and Fc NPC account for a large proportion of NPC. Importantly, immune cells including macrophages, T cells, myeloid progenitors, and neutrophils were also identified, and further analysis showed that significant intercellular interaction between macrophages and Pro NPC occurred via MIF (macrophage migration inhibitory factor) and NF-kB signaling pathways during the progression of IDD. In addition, dynamic polarization of macrophage M1 and M2 cell subtypes was found in the progression of IDD, and gene set functional enrichment analysis suggested a significant role of the macrophage polarization in regulating cell metabolism, especially the Pro NPC. Finally, we found that the NP cells in the late degenerative stage were mainly composed of the cell types related to inflammatory and endoplasmic reticulum (ER) response, and fibrocartilaginous activity. Our results provided new insights into the identification of NP cell populations at single-cell resolution and at the relatively whole-transcriptome scale, accompanied by cellular communications between immune cells and NP cells, and discriminative markers in relation to specific cell subsets. These new findings present clues for effective and functional manipulation of human IDD-related bioremediation and healthcare.

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Section: Resultsmentioning

confidence: 99%

Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in the Progression of Human Intervertebral Disc Degeneration

Ling

Liu

Wang

et al. 2022

Front. Cell Dev. Biol.

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“…TXNIP, an endogenous negative modulator of the antioxidant protein thioredoxins (TXNs), was recently reported to be closely associated with NLRP3 inflammasome activation (71). Consistent with this observation, in the cerebral venous sinus thrombosis (CVST) model, p-PERK and p-IRE1a were found to be expressed primarily in neurons; they contributed to neuronal pyroptosis by regulating TXNIP-NLRP3 inflammasome activation (72). In addition, recent research demonstrated that IRE1a could modulate NLRP1 inflammasome-mediated neuronal pyroptosis by regulating the expression of miR-125-b-2-3p (73).…”

Section: Endoplasmic Reticulum Stress and Neuronal Pyroptosismentioning

confidence: 69%

Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases

Shi

Chai²,

Zhang

et al. 2022

Front. Immunol.

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Neuronal death and inflammatory response are two common pathological hallmarks of acute central nervous system injury and chronic degenerative disorders, both of which are closely related to cognitive and motor dysfunction associated with various neurological diseases. Neurological diseases are highly heterogeneous; however, they share a common pathogenesis, that is, the aberrant accumulation of misfolded/unfolded proteins within the endoplasmic reticulum (ER). Fortunately, the cell has intrinsic quality control mechanisms to maintain the proteostasis network, such as chaperone-mediated folding and ER-associated degradation. However, when these control mechanisms fail, misfolded/unfolded proteins accumulate in the ER lumen and contribute to ER stress. ER stress has been implicated in nearly all neurological diseases. ER stress initiates the unfolded protein response to restore proteostasis, and if the damage is irreversible, it elicits intracellular cascades of death and inflammation. With the growing appreciation of a functional association between ER stress and neurological diseases and with the improved understanding of the multiple underlying molecular mechanisms, pharmacological and genetic targeting of ER stress are beginning to emerge as therapeutic approaches for neurological diseases.

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“…Txnip (Thioredoxin interacting protein) is among the gene that was significantly differentially expressed (albeit below that default 1.33-fold threshold). It was proposed a linker of ER stress and oxidative stress in the formation of inflammasome [65]. Similarly, Atg14 (Autophagy related 14), a component of the autophagy-specific membrane fusion [66] was slightly increased by ladostigil (p-value FDR = 1.2E-03).…”

Section: Ladostigil Alters the Expression Of Genes Act In Dissipating Oxidative Damagementioning

confidence: 99%

Ladostigil attenuates the oxidative and ER stress in human neuroblast-like SH-SY5Y cells

Zohar

Lezmi

Eliyahu

et al. 2021

Preprint

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A hallmark of the aging brain is the robust inflammation mediated by microglial activation. Neuroinflammation resulting from the induction of oxidative stress in neurodegenerative diseases and following brain injury. Chronic treatment of aging rats by ladostigil, a compound with antioxidant and anti-inflammatory function, prevented microglial activation and learning deficits. In this study, we investigate the effect of ladostigil on neuronal-like SH-SY5Y cells. We show that SH-SY5Y cells exposed to acute (by H2O2) or chronic oxidative stress (by Sin1, 3-morpholinosydnonimine) induced apoptotic cell death. However, in the presence of ladostigil, the decline in cell viability and the oxidative levels were partially reversed. RNA-seq analysis showed that chronic oxidation by Sin1 resulted in coordinated suppression of endoplasmic reticulum (ER) quality control and ER stress response gene sets. Chronic oxidative stress impacted ER proteostasis and induced the expression of numerous lncRNAs. Pre-incubation with ladostigil before exposing SH-SY5Y cells to Sin1 induced Clk1 (Cdc2-like kinase 1) which was implicated in psychophysiological stress in mice and Alzheimer disease. Ladostigil also suppressed the expression of Ccpg1 (Cell cycle progression 1) and Synj1 (Synaptojanin 1) that function in ER-autophagy and endocytic pathways. We postulate that ladostigil alleviated cell damage by oxidation and ER stress. Therefore, it may attenuate neurotoxicity and cell death that accompany chronic stress conditions in the aging brain.

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Endoplasmic reticulum stress and oxidative stress contribute to neuronal pyroptosis caused by cerebral venous sinus thrombosis in rats: Involvement of TXNIP/peroxynitrite-NLRP3 inflammasome activation

Cited by 30 publications

References 40 publications

Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in the Progression of Human Intervertebral Disc Degeneration

Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in the Progression of Human Intervertebral Disc Degeneration

Endoplasmic Reticulum Stress-Associated Neuronal Death and Innate Immune Response in Neurological Diseases

Ladostigil attenuates the oxidative and ER stress in human neuroblast-like SH-SY5Y cells

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