Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice

Fu, Hua; Zhao, Yanpeng; Hu, Die; Wang, Song; Yu, Tengbo; Zhang, Licheng

doi:10.1038/s41419-020-2733-4

Cited by 91 publications

(75 citation statements)

References 40 publications

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“…Microglia, astrocytes and oligodendrocyte are the main glia cells in the brain ( 96 ). These cells control the microenvironment of CNS neurons and are crucial in synaptic remodeling, tissue repair, and neuronal survival following CNS injury ( 97 – 100 ). Neuroinflammation stimulates the local activation of glia cells surrounding damaged or infected neurons.…”

Section: Neuroinflammation: At the Center Of The Infectious Hypothesimentioning

confidence: 99%

The Potential Role of Herpes Simplex Virus Type 1 and Neuroinflammation in the Pathogenesis of Alzheimer's Disease

Laval

Enquist

2021

Front. Neurol.

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Alzheimer's disease (AD) is a neurodegenerative disease affecting ~50 million people worldwide. To date, there is no cure and current therapies have not been effective in delaying disease progression. Therefore, there is an urgent need for better understanding of the pathogenesis of AD and to rethink possible therapies. Herpes simplex virus type 1 (HSV1) has recently received growing attention for its potential role in sporadic AD. The virus is a ubiquitous human pathogen that infects mucosal epithelia and invades the peripheral nervous system (PNS) of its host to establish a reactivable, latent infection. Upon reactivation, HSV1 spreads back to the epithelium and initiates a new infection, causing epithelial lesions. Occasionally, the virus spreads from the PNS to the brain after reactivation. In this review, we discuss current work on the pathogenesis of AD and summarize research results that support a potential role for HSV1 in the infectious hypothesis of AD. We also highlight recent findings on the neuroinflammatory response, which has been proposed to be the main driving force of AD, starting early in the course of the disease. Relevant rodent models to study neuroinflammation in AD and novel therapeutic approaches are also discussed. Throughout this review, we focus on several aspects of HSV1 pathogenesis, including its primary role as an invader of the PNS, that should be considered in the etiology of AD. We also point out some of the contradictory data and remaining knowledge gaps that require further research to finally fully understand the cause of AD in humans.

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Section: Neuroinflammation: At the Center Of The Infectious Hypothesimentioning

confidence: 99%

The Potential Role of Herpes Simplex Virus Type 1 and Neuroinflammation in the Pathogenesis of Alzheimer's Disease

Laval

Enquist

2021

Front. Neurol.

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“…Although unclear how COX-1 can impact persons with SCI, COX-1 is highly associated with other neurological disorders including neuroinflammation (Choi et al, 2008;Aid et al, 2010;Choi et al, 2010), Alzheimer's disease (Yermakova et al, 1999), and ischemia (Schwab et al, 2000b). Microglia are vital neuroprotective components of our central nervous system (CNS) (Streit, 2005), preventing neuron and oligodendrocyte death (Bellver-Landete et al, 2019), stripping synapses (Chen and Trapp, 2016), and increasing spinal cord repairs (Fu et al, 2020;Li et al, 2020a). Microglia can also secrete Interferon (IFN)-β to remove axon and myelin debris from the injury site (Kocur et al, 2015), increase axon regenerative potential, and improve functional locomotor recovery (Tanaka et al, 2009).…”

Section: Acute Inflammatory Changes In the Spinal Cord Following Scimentioning

confidence: 99%

The Potential Role of Inflammation in Modulating Endogenous Hippocampal Neurogenesis After Spinal Cord Injury

Sefiani

Geoffroy

2021

Front. Neurosci.

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Currently there are approximately 291,000 people suffering from a spinal cord injury (SCI) in the United States. SCI is associated with traumatic changes in mobility and neuralgia, as well as many other long-term chronic health complications, including metabolic disorders, diabetes mellitus, non-alcoholic steatohepatitis, osteoporosis, and elevated inflammatory markers. Due to medical advances, patients with SCI survive much longer than previously. This increase in life expectancy exposes them to novel neurological complications such as memory loss, cognitive decline, depression, and Alzheimer’s disease. In fact, these usually age-associated disorders are more prevalent in people living with SCI. A common factor of these disorders is the reduction in hippocampal neurogenesis. Inflammation, which is elevated after SCI, plays a major role in modulating hippocampal neurogenesis. While there is no clear consensus on the mechanism of the decline in hippocampal neurogenesis and cognition after SCI, we will examine in this review how SCI-induced inflammation could modulate hippocampal neurogenesis and provoke age-associated neurological disorders. Thereafter, we will discuss possible therapeutic options which may mitigate the influence of SCI associated complications on hippocampal neurogenesis.

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“…Second, using CCR2 null mice, it had been shown that stopping the crosstalk between resident microglia and monocyte derived macrophages participates in long-term microglial activation, greater myelin loss that eventually worsen motor function after SCI [5]. Third, complete microglia depletion altered glial scar formation, decreased immune infiltration, neuronal and oligodendrocytes survival associated with impaired motor recovery following SCI in mice [18,20]. This difference as compared to our findings may result from the specific subpopulation of microglia (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…PLX5622 treatment for 6 weeks post-SCI, improved cognition and depressive-like behavior recovery but did not improve the overall locomotor activity even if the regularity index and stride length were enhanced at 6 weeks following moderate/severe T10 contusion [60-70kdyn] [19]. PLX3397, another specific CSF1R inhibitor, given to mice between 7 days prior to complete T10 crush injury and 4 weeks after lesion impaired locomotor recovery, disorganized glial scar formation, increased lesion size, and reduced neuronal survival [20].…”

Section: Introductionmentioning

confidence: 99%

Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates

Poulen

Aloy

Bringuier

et al. 2021

Preprint

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No curative treatment is available for any deficits induced by spinal cord injury (SCI). Following injury, microglia undergo highly diverse activation processes, including proliferation, and play a critical role on functional recovery. In a translational objective, we investigated whether a transient pharmacological reduction of microglia proliferation after injury is beneficial for functional recovery after SCI in mice and nonhuman primates. The colony stimulating factor-1 receptor (CSF1R) regulates proliferation, differentiation, and survival of microglia, we thus used an oral administration of GW2580, a CSF1R inhibitor. First, transient post-injury GW2580 administration in mice improves motor function recovery, promotes tissues preservation and/or reorganization (identified by coherent anti-stokes Raman scattering microscopy), and modulates glial reactivity. Second, post-injury GW2580-treatment in nonhuman primates reduces microglia proliferation, improves functional motor function recovery, and promotes tissue protection. Notably, three months after lesion microglia reactivity returned to baseline value. Finally, to initiate the investigation on molecular mechanisms induced by a transient post-SCI GW2580-treatment, we used microglia-specific transcriptomic analysis in mice. Notably, we detected a downregulation in the expression of inflammatory-associated genes and we identified genes that were up-regulated by SCI and further downregulated by the treatment. Thus, a transient oral GW2580 treatment post-injury may provide a promising therapeutic strategy for SCI patients and may also be extended to other central nervous system disorders displaying microglia activation.

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Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice

Cited by 91 publications

References 40 publications

The Potential Role of Herpes Simplex Virus Type 1 and Neuroinflammation in the Pathogenesis of Alzheimer's Disease

The Potential Role of Herpes Simplex Virus Type 1 and Neuroinflammation in the Pathogenesis of Alzheimer's Disease

The Potential Role of Inflammation in Modulating Endogenous Hippocampal Neurogenesis After Spinal Cord Injury

Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates

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