Identification of Two Distinct Macrophage Subsets with Divergent Effects Causing either Neurotoxicity or Regeneration in the Injured Mouse Spinal Cord

Kigerl, Kristina A.; Gensel, John C.; Ankeny, Daniel P.; Alexander, Jessica K.; Donnelly, Dustin J.; Popovich, Phillip G.

doi:10.1523/jneurosci.3257-09.2009

Cited by 1,886 publications

(2,044 citation statements)

References 81 publications

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“…Previous studies also suggest that expression of M2 microglial factors promote CNS repair while limiting secondary inflammation-mediated injury after spinal cord injury. 18 Maintaining the M2 microglia/macrophage phenotype could therefore benefit the injured brain in multiple ways. 16 However, the present study reveals that the M2 phagocyte responses in both gray and white matter are transient and phased out within 7 days after injury.…”

Section: Discussionmentioning

confidence: 99%

Microglia/Macrophage Polarization Dynamics in White Matter after Traumatic Brain Injury

Wang

Zhang

et al. 2013

J Cereb Blood Flow Metab

408

331

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Mononuclear phagocytes are a population of multi-phenotypic cells and have dual roles in brain destruction/reconstruction. The phenotype-specific roles of microglia/macrophages in traumatic brain injury (TBI) are, however, poorly characterized. In the present study, TBI was induced in mice by a controlled cortical impact (CCI) and animals were killed at 1 to 14 days post injury. Real-time polymerase chain reaction (RT-PCR) and immunofluorescence staining for M1 and M2 markers were performed to characterize phenotypic changes of microglia/macrophages in both gray and white matter. We found that the number of M1-like phagocytes increased in cortex, striatum and corpus callosum (CC) during the first week and remained elevated until at least 14 days after TBI. In contrast, M2-like microglia/macrophages peaked at 5 days, but decreased rapidly thereafter. Notably, the severity of white matter injury (WMI), manifested by immunohistochemical staining for neurofilament SMI-32, was strongly correlated with the number of M1-like phagocytes. In vitro experiments using a conditioned medium transfer system confirmed that M1 microglia-conditioned media exacerbated oxygen glucose deprivation-induced oligodendrocyte death. Our results indicate that microglia/macrophages respond dynamically to TBI, experiencing a transient M2 phenotype followed by a shift to the M1 phenotype. The M1 phenotypic shift may propel WMI progression and represents a rational target for TBI treatment.

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Section: Discussionmentioning

confidence: 99%

Microglia/Macrophage Polarization Dynamics in White Matter after Traumatic Brain Injury

Wang

Zhang

et al. 2013

J Cereb Blood Flow Metab

408

331

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“…Macrophages have two distinct polarized phenotypes, M1 and M2, depending on the local tissue environment (39). In the acute stage of spinal cord injury, proinflammatory M1 macrophages dominate the lesion, but during the resolution stage, they are replaced by anti-inflammatory M2 macrophages (40). M2 macrophages produce anti-inflammatory cytokines including IL-10 (40), and several in vivo experimental studies indicate IL-10 promotes recovery after spinal cord injury (41,42).…”

Section: Discussionmentioning

confidence: 99%

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

Sekiya

Holley

Hashido

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cell transplantation therapy has long been investigated as a therapeutic intervention for neurodegenerative disorders, including spinal cord injury, Parkinson’s disease, and amyotrophic lateral sclerosis. Indeed, patients have high hopes for a cell-based therapy. However, there are numerous practical challenges for clinical translation. One major problem is that only very low numbers of donor cells survive and achieve functional integration into the host. Glial scar tissue in chronic neurodegenerative disorders strongly inhibits regeneration, and this inhibition must be overcome to accomplish successful cell transplantation. Intraneural cell transplantation is considered to be the best way to deliver cells to the host. We questioned this view with experiments in vivo on a rat glial scar model of the auditory system. Our results show that intraneural transplantation to the auditory nerve, preceded by chondroitinase ABC (ChABC)-treatment, is ineffective. There is no functional recovery, and almost all transplanted cells die within a few weeks. However, when donor cells are placed on the surface of a ChABC-treated gliotic auditory nerve, they autonomously migrate into it and recapitulate glia- and neuron-guided cell migration modes to repair the auditory pathway and recover auditory function. Surface transplantation may thus pave the way for improved functional integration of donor cells into host tissue, providing a less invasive approach to rescue clinically important neural tracts.

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“…As shown in Figure 2, A and B, rotenone exposure significantly increased the expression of markers representative of classic (inflammatory M1) activation in rat primary microglia. 31,32 Treatment of microglia with rotenone obviously enhanced the production of several proinflammatory mediators, including TNF-␣, IL-1␤, IL-6, IL-12p40, iNOS, IFN-␥, and IFN␥R. To better characterize the prop-erties of activated microglia under conditions of rotenone exposure, we further examined the expression of antiinflammatory M2 activation markers.…”

Section: Microglia Display Typical Activated Properties Under Rotenonmentioning

confidence: 99%

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Chang

Song

Jeon

et al. 2011

The American Journal of Pathology

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Rotenone exposure has emerged as an environmental risk factor for inflammation-associated neurodegenerative diseases. However, the underlying mechanisms responsible for the harmful effects of rotenone in the brain remain poorly understood. Herein, we report that myeloperoxidase (MPO) may have a potential regulatory role in rotenone-exposed brain-resident immune cells. We show that microglia, unlike neurons, do not undergo death; instead, they exhibit distinctive activated properties under rotenone-exposed conditions. Once activated by rotenone, microglia show increased production of reactive oxygen species, particularly HOCl. Notably, MPO, an HOClproducing enzyme that is undetectable under normal conditions, is significantly increased after exposure to rotenone. MPO-exposed glial cells also display characteristics of activated cells, producing proinflammatory cytokines and increasing their phagocytic activity. Interestingly, our studies with MPO inhibitors and MPO-knockout mice reveal that MPO deficiency potentiates, rather than inhibits, the rotenone-induced activated state of glia and promotes glial cell death. Furthermore, rotenone-triggered neuronal injury was more apparent in co-cultures with glial cells from Mpo ؊/؊ mice than in those from wildtype mice. Collectively, our data provide evidence that MPO has dual functionality under rotenone-exposed conditions, playing a critical regulatory role in modulating pathological and protective events in the brain.

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Identification of Two Distinct Macrophage Subsets with Divergent Effects Causing either Neurotoxicity or Regeneration in the Injured Mouse Spinal Cord

Cited by 1,886 publications

References 81 publications

Microglia/Macrophage Polarization Dynamics in White Matter after Traumatic Brain Injury

Microglia/Macrophage Polarization Dynamics in White Matter after Traumatic Brain Injury

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

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