STAT1 inhibitor alleviates spinal cord injury by decreasing apoptosis

Wu, Yuexin; Gao, Chunzheng; Fan, Kai-liang; Yang, Limin; Mei, Xifan

doi:10.4238/gmr.15017271

Cited by 5 publications

(3 citation statements)

References 19 publications

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“…In our study, in fact, we found that pSTAT1 was overexpressed in the neurons of R6/2 mice brain, as an effect of the lack of inhibition exerted by SHP-1 of which R6/2 mice neurons were devoid. Interestingly, STAT1 inhibition is able to reduce apoptotic cell death ( Wu et al, 2016 ). On the contrary, SHP-2 intensity of immunoreaction decreased with disease progression in R6/2.…”

Section: Discussionmentioning

confidence: 99%

Neuroimmune pathways involvement in neurodegeneration of R6/2 mouse model of Huntington’s disease

Paldino,

Migliorato,

Fusco

2024

Front. Cell. Neurosci.

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Mechanisms of tissue damage in Huntington’s disease (HD) involve excitotoxicity, mitochondrial damage, and neuroinflammation, including microglia activation. CD47 is a membrane protein that interacts with the inhibitory immunoreceptor SIRPα. Engagement of SIRPα by CD47 provides a downregulatory signal that inhibits host cell phagocytosis, promoting a “don’t-eat-me” signal. These proteins are involved in the immune response and are downmodulated in inflammatory diseases. The involvement of inflammation and of the inflammasome in HD has already been described. In this study, we focused on other factors that can be involved in the unregulated inflammatory response that accelerates and exacerbate the neurodegenerative process in HD. Our results show that CD47 on striatal neurons decreased in HD mice, while it increased in wild type mice with age. SIRPα, on the other hand, was present in neurons in the wild type and increases in the R6/2 mice at all stages. Recruitment of SIRPα and binding to CD47 promotes the activation through phosphorylating events of non-receptor protein tyrosine phosphatase SHP-1 and SHP-2 in neurons and microglia. SHP phosphatases are able to curb the activity of NLRP3 inflammasome thereby reducing the detrimental effect of neuroinflammation. Such activity is mediated by the inhibition (dephosphorylation) of the proteins signal transducer and activator of transcription (STAT). We found that activated SHP-1 was present in microglia and neurons of WT mice at 5 and 13 weeks, increasing with time; while in R6/2 it was not localized in neurons but only in microglia, where it decreases with time. Consequently, STAT1 was overexpressed in neurons of R6/2 mice, as an effect of lack of modulation by SHP-1. Thus, our results shed light on the pathophysiology of neuronal damage, on one hand, paving the way toward a modulation of signal transducer proteins by specific inhibitors to achieve neuroprotection in HD, on the other.

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Section: Discussionmentioning

confidence: 99%

Neuroimmune pathways involvement in neurodegeneration of R6/2 mouse model of Huntington’s disease

Paldino,

Migliorato,

Fusco

2024

Front. Cell. Neurosci.

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“…Wu et al's results indicated that selective STAT1 inhibition can reduce the injury of nerve tissue and locomotor dysfunction by regulating the inflammatory response and possible apoptosis (39). Wu et al also believed that STAT1 inhibitors reduced SCI by reducing apoptosis (40).…”

Section: Discussionmentioning

confidence: 99%

Weighted gene co-expression network analysis reveals that CXCL10, IRF7, MX1, RSAD2, and STAT1 are related to the chronic stage of spinal cord injury

Wang¹,

Liu²,

Cao³

et al. 2021

Ann Transl Med

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Background:The process of spinal cord injury involves acute, subacute, and chronic stages; however, the specific pathological mechanism remains unclear. In this study, weighted gene co-expression network analysis (WGCNA) was used to clarify specific modules and hub genes that associated with SCI. Methods:The gene expression profiles GEO Series (GSE)45006 and GEO Series (GSE)2599 were downloaded, and the co-expression network modules were identified by the WGCNA package. The proteinprotein interaction (PPI) network and Venn diagram were constructed to identify hub genes. Quantitative real-time polymerase chain reaction (QRT-PCR) was used to quantify the degree of the top five candidate genes. Correlation analysis was also carried out between hub genes and immune infiltration.Results: In total, 14,402 genes and seven modules were identified. The brown module was considered to be the most critical module for the chronic stage of SCI, which contained 775 genes that were primarily associated with various biological processes, including extracellular structure organization, lysosome, isoprenoid biosynthesis, response to nutrients, response to wounding, sulfur compound metabolic process, cofactor metabolic process, and ossification. Furthermore, C-X-C motif chemokine ligand 10 (CXCL10), myxovirus (influenza virus) resistance 1 (MX1), signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 7 (IRF7) and radical S-adenosyl methionine domain containing 2 (RSAD2) were identified as the hub genes in the PPI and Venn diagram network, and verified by qRT-PCR. Immune infiltration analysis revealed that CD8+ T cells, macrophages, neutrophils, plasmacytoid dendritic cells, helper T cells, Th2 cells, and tumor-infiltrating lymphocytes may be involved in the SCI process.Conclusions: There were significant differences among the five hub genes (CXCL10, IRF7, MX1, RSAD2, and STAT1) of the brown module, which may be potential diagnostic and prognostic markers of SCI, and immune cell infiltration may play an important role in the chronic stage of SCI.

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“…In the last two years, many research studies, focusing on the identification of drugs potentially effective in SCI treatment, have been published [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ,…”

Section: Overview Of Current Pharmacological Approaches For the Trmentioning

confidence: 99%

Nanofiber Scaffolds as Drug Delivery Systems to Bridge Spinal Cord Injury

et al. 2017

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The complex pathophysiology of spinal cord injury (SCI) may explain the current lack of an effective therapeutic approach for the regeneration of damaged neuronal cells and the recovery of motor functions. A primary mechanical injury in the spinal cord triggers a cascade of secondary events, which are involved in SCI instauration and progression. The aim of the present review is to provide an overview of the therapeutic neuro-protective and neuro-regenerative approaches, which involve the use of nanofibers as local drug delivery systems. Drugs released by nanofibers aim at preventing the cascade of secondary damage (neuro-protection), whereas nanofibrous structures are intended to re-establish neuronal connectivity through axonal sprouting (neuro-regeneration) promotion, in order to achieve a rapid functional recovery of spinal cord.

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STAT1 inhibitor alleviates spinal cord injury by decreasing apoptosis

Cited by 5 publications

References 19 publications

Neuroimmune pathways involvement in neurodegeneration of R6/2 mouse model of Huntington’s disease

Neuroimmune pathways involvement in neurodegeneration of R6/2 mouse model of Huntington’s disease

Weighted gene co-expression network analysis reveals that CXCL10, IRF7, MX1, RSAD2, and STAT1 are related to the chronic stage of spinal cord injury

Nanofiber Scaffolds as Drug Delivery Systems to Bridge Spinal Cord Injury

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