Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease

Greenhalgh, Andrew D.; Santos, Rosmarini Passos dos; Zarruk, Juan G.; Salmon, Christopher; Kroner, Antje; David, Samuel

doi:10.1016/j.bbi.2016.04.013

Cited by 57 publications

(49 citation statements)

References 29 publications

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“…We then carried out RNA-Seq analyses to determine transcriptomic changes in microglia at multiple time-points after the two SCI severities (Tables S1, S3). We found an increased expression of microglia and monocyte markers (including Arg1, Ccr2 , and Emr1 ) (Mildner et al, 2007; Gautier et al, 2012; Zhang et al, 2014; Greenhalgh et al, 2016) that were independent of lesion severity (Figure S3A, Table S3). In all samples we detected only very low expression and no lesion-induced change in neuronal ( Tubb3, Isl1, Syt1 and Gabra1 ), astrocytic ( Aldh1l1, Tnc and Aqp4 ) or oligodendrocyte ( Sox10, Mag, Mog, Mobp, Cx47 , and Cldn11 ) transcripts, further confirming the purity of our isolation procedure (Table S3).…”

Section: Resultsmentioning

confidence: 84%

“…Using these markers, Butovsky and colleagues reported clear distinctions in the transcriptomic profile of microglia and macrophages (Butovsky et al, 2014). Furthermore, a recent report suggests that Arg1 is exclusively expressed in infiltrating macrophages, but not microglia, after SCI (Greenhalgh et al, 2016). We have used CX3CR1 +/eGFP mice that express eGFP in microglia, monocytes as well as in a subsets of natural killer cells and dendritic cells (Jung et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

Noristani

Gerber

Sabourin

et al. 2017

Front. Mol. Neurosci.

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Neurons have inherent competence to regrow following injury, although not spontaneously. Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by resident microglia and infiltrating peripheral macrophages. Microglia are the first reactive glial population after SCI and participate in recruitment of monocyte-derived macrophages to the lesion site. Both positive and negative influence of microglia and macrophages on axonal regeneration had been reported after SCI, raising the issue whether their response depends on time post-lesion or different lesion severity. We analyzed molecular alterations in microglia at several time-points after different SCI severities using RNA-sequencing. We demonstrate that activation of microglia is time-dependent post-injury but is independent of lesion severity. Early transcriptomic response of microglia after SCI involves proliferation and neuroprotection, which is then switched to neuroinflammation at later stages. Moreover, SCI induces an autologous microglial expression of astrocytic markers with over 6% of microglia expressing glial fibrillary acidic protein and vimentin from as early as 72 h post-lesion and up to 6 weeks after injury. We also identified the potential involvement of DNA damage and in particular tumor suppressor gene breast cancer susceptibility gene 1 (Brca1) in microglia after SCI. Finally, we established that BRCA1 protein is specifically expressed in non-human primate spinal microglia and is upregulated after SCI. Our data provide the first transcriptomic analysis of microglia at multiple stages after different SCI severities. Injury-induced microglia expression of astrocytic markers at RNA and protein levels demonstrates novel insights into microglia plasticity. Finally, increased microglia expression of BRCA1 in rodents and non-human primate model of SCI, suggests the involvement of oncogenic proteins after CNS lesion.

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Section: Resultsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

Noristani

Gerber

Sabourin

et al. 2017

Front. Mol. Neurosci.

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“…To facilitate age-related optimization of anti-inflammatory and/or antioxidant SCI treatments, further studies are needed to determine the consequences of having more ROS producing Arg-1 macrophages in the aged injured spinal cord. In addition, although a recent publication reports that Arg-1 is exclusively expressed in infiltrating macrophages, not microglia, after SCI in young mice (Greenhalgh et al, 2016); investigations into the sources of M1 vs. M2 macrophages in older mice may give further insights in age-related neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

Age increases reactive oxygen species production in macrophages and potentiates oxidative damage after spinal cord injury

Zhang

Bailey

McVicar

et al. 2016

Neurobiology of Aging

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Age potentiates neurodegeneration and impairs recovery from spinal cord injury (SCI). Previously, we observed that age alters the balance of destructive (M1) and protective (M2) macrophages, however, the age-related pathophysiology in SCI is poorly understood. NADPH oxidase (NOX) contributes to reactive oxygen species (ROS)-mediated damage and macrophage activation in neurotrauma. Further, NOX/ROS increase with CNS age. Here, we found significantly higher ROS generation in 14 vs. 4-month-old (MO) mice after contusion SCI. Notably, NOX2 increased in 14 MO ROS-producing macrophages suggesting that macrophages and NOX contribute to SCI oxidative stress. Indicators of lipid peroxidation, a downstream cytotoxic effect of ROS accumulation, were significantly higher in 14 vs. 4 MO SCI mice. We also detected a higher percentage of ROS-producing M2 (Arginase-1-positive) macrophages in 14 vs. 4 MO mice, a previously unreported SCI phenotype, and increased M1 (CD16/32-positive) macrophages with age. Thus, NOX and ROS are age-related mediators of SCI pathophysiology and normally protective M2 macrophages may potentiate secondary injury through ROS generation in the aged injured spinal cord.

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“…In this study, we therefore consider these double-positive cells to be part of the macrophage population. The arrival of promising microglia-specific markers (Bennett et al., 2016, Greenhalgh et al., 2016) may be useful in future studies to clarify whether the double-positive cells are primarily infiltrating macrophages. It is clear that evaluation of the inflammatory infiltrate is complex, and variation occurs not only in the type of disease/trauma model but also in the time point under investigation.…”

Section: Discussionmentioning

confidence: 99%

Cell-Based Delivery of Interleukin-13 Directs Alternative Activation of Macrophages Resulting in Improved Functional Outcome after Spinal Cord Injury

et al. 2016

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SummaryThe therapeutic effects of mesenchymal stem cell (MSC) transplantation following spinal cord injury (SCI) to date have been limited. Therefore, we aimed to enhance the immunomodulatory properties of MSCs via continuous secretion of the anti-inflammatory cytokine interleukin-13 (IL-13). By using MSCs as carriers of IL-13 (MSC/IL-13), we investigated their therapeutic potential, compared with non-engineered MSCs, in a mouse model of SCI. We show that transplanted MSC/IL-13 significantly improve functional recovery following SCI, and also decrease lesion size and demyelinated area by more than 40%. Further histological analyses in CX3CR1EGFP/+ CCR2RFP/+ transgenic mice indicated that MSC/IL-13 significantly decrease the number of resident microglia and increase the number of alternatively activated macrophages. In addition, the number of macrophage-axon contacts in MSC/IL-13-treated mice was decreased by 50%, suggesting a reduction in axonal dieback. Our data provide evidence that transplantation of MSC/IL-13 leads to improved functional and histopathological recovery in a mouse model of SCI.

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Arginase-1 is expressed exclusively by infiltrating myeloid cells in CNS injury and disease

Cited by 57 publications

References 29 publications

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

Age increases reactive oxygen species production in macrophages and potentiates oxidative damage after spinal cord injury

Cell-Based Delivery of Interleukin-13 Directs Alternative Activation of Macrophages Resulting in Improved Functional Outcome after Spinal Cord Injury

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