Microglia: active sensor and versatile effector cells in the normal and pathologic brain

Hanisch, Uwe‐Karsten; Kettenmann, Helmut

doi:10.1038/nn1997

Cited by 3,202 publications

(2,853 citation statements)

References 99 publications

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“…The function of this interaction between apoE and LRP1, has been associated with suppression of neuroinflammation 57. Microglial cells, which expresses LRP1, are resident macrophages within the CNS that become activated in pathological situations, including cerebral ischemia 58. Microglial activation results in oxidative stress and the release of inflammatory mediators, contributing to BBB breakdown, secondary neuronal injury, and development of cerebral edema 59.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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ObjectiveAt present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti‐inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN‐105, in a microglial cell line and murine model of ischemic stroke.MethodsTen to 13‐week‐old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN‐105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor‐sensory functional outcomes using rotarod test and 4‐limb wire hanging test, infarct volume assessment using 2,3,5‐Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor‐alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN‐105 in ischemic stroke.ResultsMice receiving CN‐105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN‐105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN‐105 reduces proinflammatory pathways and lower oxidative stress.Interpretation CN‐105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN‐105 represents an attractive candidate for clinical translation.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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“…To distinguish resident microglia and blood‐derived macrophages in ischemic brain injury, several studies have been performed using transplanted bone marrow cells from a mouse ubiquitously expressing GFP under the control of a beta‐actin promoter after depleting the intrinsic monocyte population by irradiation (Schilling et al, 2003; Tanaka et al, 2003). A disadvantage with this approach is the possibility that the irradiation used to deplete the endogenous bone marrow may affect the BBB and augment cell infiltration (Hanisch and Kettenmann, 2007). To circumvent this, a recent report employed cranium‐shielded irradiation in bone marrow chimera experiments when addressing the role of blood‐derived macrophages in ischemic stroke, concluding that blood‐derived macrophages recruited via Ccr2 are essential for maintaining integrity of the neurovascular unit following brain ischemia (Gliem et al, 2012), at least in adult mice.…”

Section: Discussionmentioning

confidence: 99%

“…To circumvent this, a recent report employed cranium‐shielded irradiation in bone marrow chimera experiments when addressing the role of blood‐derived macrophages in ischemic stroke, concluding that blood‐derived macrophages recruited via Ccr2 are essential for maintaining integrity of the neurovascular unit following brain ischemia (Gliem et al, 2012), at least in adult mice. However, Hanisch et al mentioned that myeloid precursors may be artificially mobilized into circulation by transplantation of bone marrow, which is not physiological (Hanisch and Kettenmann, 2007). Dénes et al demonstrated that there were no significant changes in the ischemic brain damage between Cx3cr1 GFP/+ and wild type mice, and Saederup et al showed that monocyte/macrophage recruitment after thioglycollate‐induced peritonitis was not significantly changed between Cx3cr1 GFP/+ Ccr2 RFP/+ and wild type mice (Dénes et al, 2008; Saederup et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

Umekawa

Osman

Han

et al. 2015

Glia

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The mechanisms of neuronal injury after hypoxia–ischemia (HI) are different in the immature and the adult brain, but microglia activation has not been compared. The purpose of this study was to phenotype resident microglia and blood‐derived macrophages in the hippocampus after HI in neonatal (postnatal day 9, P9) or adult (3 months of age, 3mo) mice. Unilateral brain injury after HI was induced in Cx3cr1GFP/+Ccr2RFP/+ male mice on P9 (n = 34) or at 3mo (n = 53) using the Vannucci model. Resident microglia (Cx3cr1‐GFP+) proliferated and were activated earlier after HI in the P9 (1–3 days) than that in the 3mo hippocampus, but remained longer in the adult brain (3–7 days). Blood‐derived macrophages (Ccr2‐RFP+) peaked 3 days after HI in both immature (P9) and adult (3mo) hippocampi but were twice as frequent in adult brains, 41% vs. 21% of all microglia/macrophages. CCL2 expression was three times higher in the P9 hippocampi, indicating that the proinflammatory response was more pronounced in the immature brain after HI. This corresponded well with the higher numbers of galectin‐3‐positive resident microglia in the P9 hippocampi, but did not correlate with CD16/32‐ or CD206‐positive resident microglia or blood‐derived macrophages. In conclusion, resident microglia, rather than infiltrating blood‐derived macrophages, proliferate and are activated earlier in the immature than in the adult brain, but remain increased longer in the adult brain. The inflammatory response is more pronounced in the immature brain, and this correlate well with galectin‐3 expression in resident microglia. GLIA 2015;63:2220–2230

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“…Microglia “at rest” are highly dynamic cells, constantly extending and retracting their processes to sample the local environment via a variety of receptors, including pattern recognition, purinergic, and scavenger receptors (Hanisch & Kettenmann, 2007; Nimmerjahn, Kirchhoff, & Helmchen, 2005). In addition to their immunocompetency, studies implicate microglia in maintaining tissue homeostasis and synaptic connectivity (Kettenmann, Kirchhoff, & Verkhratsky, 2013).…”

Section: Introductionmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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Microglia: active sensor and versatile effector cells in the normal and pathologic brain

Cited by 3,202 publications

References 99 publications

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

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