Emerging Roles of Microglia Depletion in the Treatment of Spinal Cord Injury

Deng, Junhao; Meng, Fanqi; Zhang, Kexue; Gao, Jianpeng; Liu, Zhongyang; Li, Ming; Liu, Xiao; Li, Jiantao; Wang, Yu; Zhang, Licheng; Tang, Peifu

doi:10.3390/cells11121871

Cited by 23 publications

(9 citation statements)

References 75 publications

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“…Different major pharmacological approaches are now in use to investigate macrophage and microglia functions during CNS injury response such as CSF1R inhibitors (e.g., PLX5622 and PLX3397). CSF1R inhibitors have been suggested to selectively deplete CNS microglia without a significant impact on peripheral immune cells [ 96 – 98 ]. Nevertheless, their influence extends beyond microglia, encompassing lasting alterations within the myeloid populations of the bone marrow, spleen, and bloodstream [ 99 ].…”

Section: Discussionmentioning

confidence: 99%

Macrophages coordinate immune response to laser-induced injury via extracellular traps

Conedera,

Kokona,

Zinkernagel

et al. 2024

J Neuroinflammation

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Background Retinal degeneration results from disruptions in retinal homeostasis due to injury, disease, or aging and triggers peripheral leukocyte infiltration. Effective immune responses rely on coordinated actions of resident microglia and recruited macrophages, critical for tissue remodeling and repair. However, these phagocytes also contribute to chronic inflammation in degenerated retinas, yet the precise coordination of immune response to retinal damage remains elusive. Recent investigations have demonstrated that phagocytic cells can produce extracellular traps (ETs), which are a source of self-antigens that alter the immune response, which can potentially lead to tissue injury. Methods Innovations in experimental systems facilitate real-time exploration of immune cell interactions and dynamic responses. We integrated in vivo imaging with ultrastructural analysis, transcriptomics, pharmacological treatments, and knockout mice to elucidate the role of phagocytes and their modulation of the local inflammatory response through extracellular traps (ETs). Deciphering these mechanisms is essential for developing novel and enhanced immunotherapeutic approaches that can redirect a specific maladaptive immune response towards favorable wound healing in the retina. Results Our findings underscore the pivotal role of innate immune cells, especially macrophages/monocytes, in regulating retinal repair and inflammation. The absence of neutrophil and macrophage infiltration aids parenchymal integrity restoration, while their depletion, particularly macrophages/monocytes, impedes vascular recovery. We demonstrate that macrophages/monocytes, when recruited in the retina, release chromatin and granular proteins, forming ETs. Furthermore, the pharmacological inhibition of ETosis support retinal and vascular repair, surpassing the effects of blocking innate immune cell recruitment. Simultaneously, the absence of ETosis reshapes the inflammatory response, causing neutrophils, helper, and cytotoxic T-cells to be restricted primarily in the superficial capillary plexus instead of reaching the damaged photoreceptor layer. Conclusions Our data offer novel insights into innate immunity's role in responding to retinal damage and potentially help developing innovative immunotherapeutic approaches that can shift the immune response from maladaptive to beneficial for retinal regeneration.

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Section: Discussionmentioning

confidence: 99%

Macrophages coordinate immune response to laser-induced injury via extracellular traps

Conedera,

Kokona,

Zinkernagel

et al. 2024

J Neuroinflammation

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“…After SCI, microglia and astrocytes are rapidly activated by various pathological factors. Then activated microglia release IL-1β, IL-6 and TNF-α, causing a large number of nerve cell death, axonal degeneration, demyelination [22]. Glial scars include both brous and glial components, and astrocytes and microglia are involved in glial formation [23].…”

Section: Discussionmentioning

confidence: 99%

UAMC-3203 improves the inhibitory microenvironment to repair spinal cord injury by inhibiting ferroptosis

Kan

Zhao

Liu

et al. 2022

Preprint

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Background: Spinal cord injury (SCI) is a type of trauma to the nervous system that can lead to severe dysfunction of the motor and sensory systems. The inhibitory microenvironment is the basis of secondary injury after SCI, and ferroptosis may aggravate secondary SCI. In this study, the role of ferroptosis inhibitor UAMC-3203 in the recovery of SCI was explored by examining the tissue structure, biochemical indexes, and motor function of rats after SCI. Methods: A model of SCI was established using Alice's method. The protective effect of UAMC-3203 on spinal cord neurons and the recovery of motor function were studied by Basso, Beattie, Bresnahan (BBB) score, incline plate test, Hematoxylin-eosin (HE) staining and Luxol Fast Blue (LFB) staining. Immunofluorescence and Elisa analysis were used to study the effect of UAMC-3203 on the microenvironment. Western blot analysis was used to measure the level of ferroptosis markers. Reactive oxygen species (ROS) and malondialdehyde (MDA) were detected to reflect the level of oxidation products. Results: We found that in the UAMC-3203 group, the loss and demyelination of neurons was reduced, the activation and proliferation of astrocytes and microglia and the secretion of related inflammatory cytokines was restrained, and motor function recovery was faster and better compared with those in the SCI group. Conclusions: UAMC-3203 has played an active role in the recovery process of SCI, providing evidence that post-SCI microenvironment imbalances are associated with ferroptosis.

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“…Thirdly, microglial depletion strategies in SCI animal models have yielded beneficial and detrimental effects on scarring, axonal regeneration, and functional recovery ( Deng et al, 2022 ). Microglia primarily exert their beneficial functions within the first week of SCI, while activation beyond this phase proves harmful ( Zhou X. et al, 2020 ).…”

Section: Microgliamentioning

confidence: 99%

Tackling the glial scar in spinal cord regeneration: new discoveries and future directions

Shafqat

Albalkhi

Magableh

et al. 2023

Front. Cell. Neurosci.

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Axonal regeneration and functional recovery are poor after spinal cord injury (SCI), typified by the formation of an injury scar. While this scar was traditionally believed to be primarily responsible for axonal regeneration failure, current knowledge takes a more holistic approach that considers the intrinsic growth capacity of axons. Targeting the SCI scar has also not reproducibly yielded nearly the same efficacy in animal models compared to these neuron-directed approaches. These results suggest that the major reason behind central nervous system (CNS) regeneration failure is not the injury scar but a failure to stimulate axon growth adequately. These findings raise questions about whether targeting neuroinflammation and glial scarring still constitute viable translational avenues. We provide a comprehensive review of the dual role of neuroinflammation and scarring after SCI and how future research can produce therapeutic strategies targeting the hurdles to axonal regeneration posed by these processes without compromising neuroprotection.

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Emerging Roles of Microglia Depletion in the Treatment of Spinal Cord Injury

Cited by 23 publications

References 75 publications

Macrophages coordinate immune response to laser-induced injury via extracellular traps

Macrophages coordinate immune response to laser-induced injury via extracellular traps

UAMC-3203 improves the inhibitory microenvironment to repair spinal cord injury by inhibiting ferroptosis

Tackling the glial scar in spinal cord regeneration: new discoveries and future directions

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