The role of transglutaminase 2 in mediating glial cell function and pathophysiology in the central nervous system

Rudlong, Jacob; Cheng, Anson; Johnson, Gail V.W.

doi:10.1016/j.ab.2019.113556

Cited by 15 publications

(18 citation statements)

References 83 publications

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“…Although it is clear that astrocytes can take on either supportive or harmful phenotypes after injury, the cell autonomous determinants that direct astrocytes towards either phenotype have not been well defined. Recently, we have identified transglutaminase 2 (TG2) as a key factor in determining the molecular response of astrocytes to injury [ 6 , 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

Elahi

Emerson

Rudlong

et al. 2021

Cells

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Following CNS injury, astrocytes become “reactive” and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here, we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/− TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days post-injury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis revealed a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron–astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.

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Section: Introductionmentioning

confidence: 99%

Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

Elahi

Emerson

Rudlong

et al. 2021

Cells

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“…These molecular functions of TGM2 participate in the regulation of diverse pathophysiological processes such as wound healing, cell growth, cell differentiation, cell apoptosis, extracellular microenvironment, autophagy, and tumor initiation and progression [14][15][16][17][18]. TGM2 is implicated in modulating glial cell function such as astrocytes, microglia, and oligodendrocytes and contributes to pathophysiology in the central nervous system (CNS) [19]. Previously, it has been reported that an increase of TGM2 expression facilitates the generation of inducible nitric oxide synthase (iNOS), which might induce neuronal death [20].…”

Section: Introductionmentioning

confidence: 99%

Propofol Suppresses Microglia Inflammation by Targeting TGM2/NF-κB Signaling

Hou

Xiao

et al. 2021

Journal of Immunology Research

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Background. Propofol is a known intravenous hypnotic drug used for induction and maintenance of sedation and general anesthesia. Emerging studies also reveal a neuroprotective effect of propofol in diverse diseases of neuronal injuries via modulating microglia activation. In this study, we aimed to uncover the downstream targets of propofol in this process. Methods. RNA sequencing analysis to identify genes implicated in the propofol-mediated neuroprotective effect. Quantitative real-time PCR, enzyme-linked immunosorbent assay, and Western blotting analysis were performed to analyze inflammatory gene expression, cytokine levels, and TGM2. BV2 cells and primary microglia were used for functional verification and mechanism studies. Results. The multifunctional enzyme transglutaminase 2 (TGM2) was identified as a putative functional mediator of propofol. TGM2 was significantly upregulated in lipopolysaccharide- (LPS-) primed BV2 cells. Genetic silencing of TGM2 abolished LPS-induced microglial activation. Notably, gain-of-function experiments showed that the proinflammatory effects of TGM2 were dependent on its GTP binding activity instead of transamidase activity. Then, TGM2 was revealed to activate the NF-κB signaling pathway to facilitate microglial activation. Propofol can inhibit TGM2 expression and NF-κB signaling in BV2 cells and primary microglia. Ectopic expression of TGM2 or constitutively active IKKβ (CA-IKKβ) can compromise propofol-induced anti-inflammatory effects. Conclusions. Our findings suggest that TGM2-mediated activation of NF-κB signaling is an important mechanism in the propofol-induced neuroprotective effect that prevents microglial activation.

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“…As TG2 is rapidly upregulated in astrocytes in response to CNS injury [9], we next examined histological measures of CNS injury and reactive gliosis in spinal cord sections from mice at 3 and 7 dpi. GFAP immunoreactivity was significantly reduced both 2 mm proximal (−2 mm) and at the epicenter of the injury in TG2-A-cKO mice compared to TG2fl/fl mice that express normal levels of astrocytic TG2.…”

Section: Resultsmentioning

confidence: 99%

Deletion or inhibition of astrocytic transglutaminase 2 promotes functional recovery after spinal cord injury

Elahi

Emerson

Rudlong

et al. 2021

Preprint

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Following CNS injury astrocytes become reactive and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/- TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days postinjury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis reveals a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron-astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.

show abstract

The role of transglutaminase 2 in mediating glial cell function and pathophysiology in the central nervous system

Cited by 15 publications

References 83 publications

Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

Propofol Suppresses Microglia Inflammation by Targeting TGM2/NF-κB Signaling

Deletion or inhibition of astrocytic transglutaminase 2 promotes functional recovery after spinal cord injury

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