G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice

Guo, Yongfeng; Liu, Shangming; Zhang, Xianghong; Wang, Liyan; Gao, Jiangang; Han, Aiqing; Hao, Aijun

doi:10.1038/labinvest.2015.120

Cited by 29 publications

(18 citation statements)

References 54 publications

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“…Moreover, G-CSF has a neuroprotective effect in several murine models of acute spinal cord injury. For instance, this cytokine is able to rapidly induce autophagy after spinal cord injury to inhibit neuronal apoptosis and is considered an effective auxiliary therapeutic intervention for spinal cord injury (50). However, sustained levels of IL-6 and G-CSF can overwhelm the immune response and can be detrimental for the host.…”

Section: Discussionmentioning

confidence: 99%

Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice

Laval

Vernejoul

Cleemput

et al. 2018

J Virol

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Pseudorabies virus (PRV) is an alphaherpesvirus that infects the peripheral nervous system (PNS). The natural host of PRV is the swine, but it can infect most mammals, including cattle, rodents, and dogs. In these nonnatural hosts, PRV always causes a severe acute and lethal neuropathy called the "mad itch," which is uncommon in swine. Thus far, the pathophysiological and immunological processes leading to the development of the neuropathic itch and the death of the animal are unclear. Using a footpad inoculation model, we established that mice inoculated with PRV-Becker (virulent strain) develop a severe pruritus in the foot and become moribund at 82 h postinoculation (hpi). We found necrosis and inflammation with a massive neutrophil infiltration only in the footpad and dorsal root ganglia (DRGs) by hematoxylin and eosin staining. PRV load was detected in the foot, PNS, and central nervous system tissues by quantitative reverse transcription-PCR. Infected mice had elevated plasma levels of proinflammatory cytokines (interleukin-6 [IL-6] and granulocyte colony-stimulating factor [G-CSF]) and chemokines (Gro-1 and monocyte chemoattractant protein 1). Significant IL-6 and G-CSF levels were detected in several tissues at 82 hpi. High plasma levels of C-reactive protein confirmed the acute inflammatory response to PRV-Becker infection. Moreover, mice inoculated with PRV-Bartha (attenuated, live vaccine strain) did not develop pruritus at 82 hpi. PRV-Bartha also replicated in the PNS, and the infection spread further in the brain than PRV-Becker. PRV-Bartha infection did not induce the specific and lethal systemic inflammatory response seen with PRV-Becker. Overall, we demonstrated the importance of inflammation in the clinical outcome of PRV infection in mice and provide new insights into the process of PRV-induced neuroinflammation.IMPORTANCE Pseudorabies virus (PRV) is an alphaherpesvirus related to human pathogens such as herpes simplex virus 1 and varicella-zoster virus (VZV). The natural host of PRV is the swine, but it can infect most mammals. In susceptible animals other than pigs, PRV infection always causes a characteristic lethal pruritus known as the "mad itch." The role of the immune response in the clinical outcome of PRV infection is still poorly understood. Here, we show that a systemic host inflammatory response is responsible for the severe pruritus and acute death of mice infected with virulent PRV-Becker but not mice infected with attenuated strain PRV-Bartha. In addition, we identified IL-6 and G-CSF as two main cytokines that play crucial roles in the regulation of this process. Our findings give new insights into neuroinflammatory diseases and strengthen further the similarities between VZV and PRV infections at the level of innate immunity. Citation Laval K, Vernejoul JB, Van Cleemput J, Koyuncu OO, Enquist LW. 2018. Virulent pseudorabies virus infection induces a specific and lethal systemic inflammatory response in mice. J Virol 92:e01614-18. https://doi.org/10 .1128/JVI.01614-18. Editor Ric...

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Section: Discussionmentioning

confidence: 99%

Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice

Laval

Vernejoul

Cleemput

et al. 2018

J Virol

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“…**p \ 0.01; ***p \ 0.001 compared to MSC:SC 0.1 tissues and organs, we generated MSC cell lines expressing G-CSF and IGF-1. Several reports have shown the potential therapeutic use of G-CSF in regenerative medicine, including cardiac (Harada et al 2005;Ieishi et al 2007;Macambira et al 2009), neurological (Huang and Tsai 2014;Guo et al 2015) and hepatic diseases (Yang et al 2016). The immunomodulatory potential of G-CSF suggests that transgenic MSC expressing this growth factor may also contribute to the modulation of inflammation at the site of transplantation.…”

Section: Discussionmentioning

confidence: 99%

Generation and characterization of transgenic mouse mesenchymal stem cell lines expressing hIGF-1 or hG-CSF

et al. 2017

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Mesenchymal stem cells (MSC) are promising tools in the fields of cell therapy and regenerative medicine. In addition to their differentiation potential, MSC have the ability to secrete bioactive molecules that stimulate tissue regeneration. Thus, the overexpression of cytokines and growth factors may enhance the therapeutic effects of MSC. Here we generated and characterized mouse bone marrow MSC lines overexpressing hG-CSF or hIGF-1. MSC lines overexpressing hG-CSF or hIGF-1 were generated through lentiviral vector mediated gene transfer. The expression of hG-CSF or hIGF-1 genes in the clones produced was quantified by qRT-PCR, and the proteins were detected in the cell supernatants by ELISA. The cell lines displayed cell surface markers and differentiation potential into adipocytes, osteocytes and chondrocytes similar to the control MSC cell lines, indicating the conservation of their phenotype even after genetic modification. IGF-1 and G-CSF transgenic cells maintained immunosuppressive activity. Finally, we performed a comparative gene expression analysis by qRT-PCR array in the cell lines expressing hIGF-1 and hG-CSF when compared to the control cells. Our results demonstrate that the cell lines generated may be useful tools for cell therapy and are suitable for testing in disease models.

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“…In these studies, it was believed that upregulation of autophagy after administration of these therapeutic agents supports the hypothesis that autophagy exerts a protective effect [97], and the downregulation of autophagy supports the contrary [73]. However, both upregulation and downregulation of autophagy in SCI were found after administration of various therapeutic agents (Table 1).…”

Section: Pharmacological Intervention Of Autophagy In Scimentioning

confidence: 91%

“…In hemisection injury, granulocyte colony-stimulating factor, a low molecular weight glycoprotein, was found to increase autophagy activity and provide a therapeutic intervention in SCI via inhibiting neuronal apoptosis [97]. The active metabolite of vitamin A, retinoic acid, inhibits endoplasmic reticulum-stress (ER-stress) dependent apoptosis, prevents disruption of the blood-spinal cord barrier, and upregulates autophagy after hemisection injury as well [75].…”

Section: Pharmacological Intervention Of Autophagy In Scimentioning

confidence: 99%

The Temporal Pattern, Flux, and Function of Autophagy in Spinal Cord Injury

Zhou

Sansur

et al. 2017

IJMS

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Previous studies have indicated that autophagy plays a critical role in spinal cord injury (SCI), including traumatic spinal cord injury (TSCI) and ischemia-reperfusion spinal cord injury (IRSCI). However, while the understanding of mechanisms underlying autophagy in SCI has progressed, there remain several controversial points: (1) temporal pattern results of autophagic activation after SCI are not consistent across studies; (2) effect of accumulation of autophagosomes due to the blockade or enhancement of autophagic flux is uncertain; (3) overall effect of enhanced autophagy remains undefined, with both beneficial and detrimental outcomes reported in SCI literature. In this review, the temporal pattern of autophagic activation, autophagic flux, autophagic cell death, relationship between autophagy and apoptosis, and pharmacological intervention of autophagy in TSCI (contusion injury, compression injury and hemisection injury) and IRSCI are discussed. Types of SCI and severity appear to contribute to differences in outcomes regarding temporal pattern, flux, and function of autophagy. With future development of specific strategies on autophagy intervention, autophagy may play an important role in improving functional recovery in patients with SCI.

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G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice

Cited by 29 publications

References 54 publications

Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice

Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice

Generation and characterization of transgenic mouse mesenchymal stem cell lines expressing hIGF-1 or hG-CSF

The Temporal Pattern, Flux, and Function of Autophagy in Spinal Cord Injury

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