Function of microglia and macrophages in secondary damage after spinal cord injury

Zhou, Xiang; He, Xijing; Ren, Yi

doi:10.4103/1673-5374.143423

Cited by 218 publications

(74 citation statements)

References 122 publications

(150 reference statements)

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“…Furthermore, microglia and peripherally derived macrophages may exert slightly different functions. Recent studies demonstrated divergent spatial distributions, with microglia surrounding injury center and macrophages concentrating at lesion core after SCI 33 , 34 . Whether HDAC3 plays distinct roles in these two populations awaits future studies.…”

Section: Discussionmentioning

confidence: 99%

HDAC3 inhibition ameliorates spinal cord injury by immunomodulation

Kuboyama

Wahane

Huang

et al. 2017

Sci Rep

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Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair.

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Section: Discussionmentioning

confidence: 99%

HDAC3 inhibition ameliorates spinal cord injury by immunomodulation

Kuboyama

Wahane

Huang

et al. 2017

Sci Rep

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“…The innate immune reaction produced by microglia/macrophages has been demonstrated to contribute to the cavity formation and enlargement after SCI [ 7 ]. The destructive effects of activated microglia/macrophages were largely attributed to their M1 sub-group, which was activated quickly after SCI and expressed high levels of pro-inflammatory cytokines, including the well-studied necroptosis inducing factor TNFα [ 23 , 37 ]. It is therefore reasonable to speculate a link between M1 micorglia/macrophages and astrocyte death after SCI, which has been poorly investigated.…”

Section: Discussionmentioning

confidence: 99%

Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury

Fan

Zhang

Shan

et al. 2016

Mol Neurodegeneration

184

143

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BackgroundA unique feature of the pathological change after spinal cord injury (SCI) is the progressive enlargement of lesion area, which usually results in cavity formation and is accompanied by reactive astrogliosis and chronic inflammation. Reactive astrocytes line the spinal cavity, walling off the lesion core from the normal spinal tissue, and are thought to play multiple important roles in SCI. The contribution of cell death, particularly the apoptosis of neurons and oligodendrocytes during the process of cavitation has been extensively studied. However, how reactive astrocytes are eliminated following SCI remains largely unclear.ResultsBy immunohistochemistry, in vivo propidium iodide (PI)-labeling and electron microscopic examination, here we reported that in mice, reactive astrocytes died by receptor-interacting protein 3 and mixed lineage kinase domain-like protein (RIP3/MLKL) mediated necroptosis, rather than apoptosis or autophagy. Inhibiting receptor-interacting protein 1 (RIP1) or depleting RIP3 not only significantly attenuated astrocyte death but also rescued the neurotrophic function of astrocytes. The astrocytic expression of necroptotic markers followed the polarization of M1 microglia/macrophages after SCI. Depleting M1 microglia/macrophages or transplantation of M1 macrophages could significantly reduce or increase the necroptosis of astrocytes. Further, the inflammatory responsive genes Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) are induced in necroptotic astrocytes. In vitro antagonizing MyD88 in astrocytes could significantly alleviate the M1 microglia/macrophages-induced cell death. Finally, our data showed that in human, necroptotic markers and TLR4/MyD88 were co-expressed in astrocytes of injured, but not normal spinal cord.ConclusionTaken together, these results reveal that after SCI, reactive astrocytes undergo M1 microglia/macrophages-induced necroptosis, partially through TLR/MyD88 signaling, and suggest that inhibiting astrocytic necroptosis may be beneficial for preventing secondary SCI.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0081-8) contains supplementary material, which is available to authorized users.

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“…Detrimental inflammatory responses in the central nervous system (CNS) are a hallmark of various neurodegenerative pathologies, with multiple sclerosis (MS), stroke and traumatic brain or spinal cord injury being excellent examples of the complex interplay between CNS-resident microglia and lesion-infiltrating leukocytes [1–4]. Although microglia and CNS-invading peripheral monocytes both act as phagocytic cells of the brain, it is currently becoming accepted that these two cell types are more distinct than generally assumed [2, 5].…”

Section: Introductionmentioning

confidence: 99%

Intracerebral transplantation of interleukin 13-producing mesenchymal stem cells limits microgliosis, oligodendrocyte loss and demyelination in the cuprizone mouse model

Blon

Guglielmetti

Hoornaert

et al. 2016

J Neuroinflammation

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BackgroundPromoting the neuroprotective and repair-inducing effector functions of microglia and macrophages, by means of M2 polarisation or alternative activation, is expected to become a new therapeutic approach for central nervous system (CNS) disorders in which detrimental pro-inflammatory microglia and/or macrophages display a major contribution to the neuropathology. In this study, we present a novel in vivo approach using intracerebral grafting of mesenchymal stem cells (MSC) genetically engineered to secrete interleukin 13 (IL13-MSC).MethodsIn the first experimental setup, control MSC and IL13-MSC were grafted in the CNS of eGFP+ bone marrow chimaeric C57BL/6 mice to histologically evaluate IL13-mediated expression of several markers associated with alternative activation, including arginase1 and Ym1, on MSC graft-recognising microglia and MSC graft-infiltrating macrophages. In the second experimental setup, IL13-MSC were grafted on the right side (or on both the right and left sides) of the splenium of the corpus callosum in wild-type C57BL/6 mice and in C57BL/6 CX3CR1eGFP/+CCR2RFP/+ transgenic mice. Next, CNS inflammation and demyelination was induced by means of a cuprizone-supplemented diet. The influence of IL13-MSC grafting on neuropathological alterations was monitored by non-invasive T 2-weighted magnetic resonance imaging (MRI) and quantitative histological analyses, as compared to cuprizone-treated mice with control MSC grafts and/or cuprizone-treated mice without MSC injection.ResultsIn the first part of this study, we demonstrate that MSC graft-associated microglia and MSC graft-infiltrating macrophages are forced into alternative activation upon grafting of IL13-MSC, but not upon grafting of control MSC. In the second part of this study, we demonstrate that grafting of IL13-MSC, in addition to the recruitment of M2 polarised macrophages, limits cuprizone-induced microgliosis, oligodendrocyte death and demyelination. Furthermore, we here demonstrate that injection of IL13-MSC at both sides of the splenium leads to a superior protective effect as compared to a single injection at one side of the splenium.ConclusionsControlled and localised production of IL13 by means of intracerebral MSC grafting has the potential to modulate cell graft- and pathology-associated microglial/macrophage responses, and to interfere with oligodendrocyte death and demyelinating events in the cuprizone mouse model.

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Function of microglia and macrophages in secondary damage after spinal cord injury

Cited by 218 publications

References 122 publications

HDAC3 inhibition ameliorates spinal cord injury by immunomodulation

HDAC3 inhibition ameliorates spinal cord injury by immunomodulation

Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury

Intracerebral transplantation of interleukin 13-producing mesenchymal stem cells limits microgliosis, oligodendrocyte loss and demyelination in the cuprizone mouse model

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