Robust increase of microglia proliferation in the fornix of hippocampal axonal pathway after a single LPS stimulation

Fukushima, Shohei; Furube, Eriko; Itoh, Masanobu; Nakashima, Toshihiro; Miyata, Seiji

doi:10.1016/j.jneuroim.2015.05.014

Cited by 35 publications

(26 citation statements)

References 44 publications

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“…We observed an increase in Iba‐1 + cell number after systemic LPS. This increase might have been caused by cell proliferation as has been shown in the hippocampus after a single systemic LPS injection (Fukushima et al , ) or by infiltration of peripheral monocytes or migration of microglia cells from one area to another. Further experiments will elucidate the effect of systemic LPS on microglia cells in striatum and substantia nigra as well as the role of VAP‐1 inhibition on microglia response.…”

Section: Discussionmentioning

confidence: 85%

Inhibition of semicarbazide‐sensitive amine oxidase/vascular adhesion protein‐1 reduces lipopolysaccharide‐induced neuroinflammation

Becchi

Buson

Foot

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSENeuroinflammation is initiated by a variety of stimuli including infections, sepsis, neurodegenerative diseases or traumatic brain injury and, if not adequately controlled, can lead to various degrees of neuronal damage and behavioural impairment. A critical event in the initial steps of inflammation is neutrophil extravasation. Semicarbazide-sensitive amine oxidase (SSAO, also known as vascular adhesion protein 1 or VAP-1) regulates neutrophil adhesion and extravasation. Here, we elucidate the role of SSAO/VAP-1 in the early stage inflammatory response after LPS insult in the brain. EXPERIMENTAL APPROACHPXS-4681A, a selective and irreversible SSAO/VAP-1 inhibitor, was tested in two rat models of neuroinflammation, following systemic or i.c.v. LPS. Immunohistochemical and immunofluorescence techniques were used to measure neutrophils and microglia. VAP-1 was quantitated by Western blotting. KEY RESULTSBoth systemic and i.c.v. administration of LPS induced an increase in neutrophil recruitment and microglial response in various brain areas including the substantia nigra and striatum. PXS-4681A produced a significant inhibition of neutrophil recruitment and extravasation after i.c.v. LPS injection and also reversed microglial cell recruitment and morphological changes to the level of the sham controls in both LPS models. CONCLUSIONS AND IMPLICATIONSPXS-4681A acted as an effective anti-inflammatory agent after both systemic and i.c.v. LPS injections suggesting that SSAO/VAP-1 inhibition could be beneficial in the treatment of brain inflammation. AbbreviationsBBB, blood-brain barrier; BCA, bicinchoninic acid; DAB, 3,3 0 -diaminobenzidine; Iba-1, ionized calcium-binding adapter molecule 1; MPO, myeloperoxidase; PFA, paraformaldehyde; RECA-1, rat endothelial cell antibody 1; SSAO, semicarbazidesensitive amine oxidase; VAP-1, vascular adhesion protein 1

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Section: Discussionmentioning

confidence: 85%

Inhibition of semicarbazide‐sensitive amine oxidase/vascular adhesion protein‐1 reduces lipopolysaccharide‐induced neuroinflammation

Becchi

Buson

Foot

et al. 2017

British J Pharmacology

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“…Microglial proliferation in the adult rodent brains is slow with increases at a rate of only a few percent per week under physiologically healthy conditions 1 , 7 , 8 . In the mouse and human brain, the microglial density remains remarkably stable, but microglia turnover several times during a lifetime 9 .…”

Section: Introductionmentioning

confidence: 99%

Brain Region-dependent Heterogeneity and Dose-dependent Difference in Transient Microglia Population Increase during Lipopolysaccharide-induced Inflammation

Furube¹,

Kawai²,

Inagaki³

et al. 2018

Sci Rep

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112

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Numerous studies have reported the importance of microglial activation in various pathological conditions, whereas little attention has been given to the point for dynamics of microglial population under infection-induced inflammation. In the present study, the single systemic stimulation of 100 μg/kg lipopolysaccharide (LPS) induced robust microglial proliferation only in the circumventricular organs (CVOs) and their neighboring brain regions. More than half of microglia similarly showed proliferative activity in the CVOs and their neighboring brain regions after 1 mg/kg LPS stimulation, while this stimulation expanded microglia-proliferating brain regions including the hypothalamus, medulla oblongata, and limbic system. Microglia proliferation resulted in a transient increase of microglial density, since their density almost returned to basal levels within 3 weeks. Divided microglia survived at the same rate as non-divided ones. Proliferating microglia frequently expressed a resident microglia marker Tmem119, indicating that increase of microglia density is due to the proliferation of resident microglia. Thus, the present study demonstrates that transient increase in microglia density depends on the brain region and dose of LPS during infection-induced inflammation and could provide a new insight on microglia functions in inflammation and pathogenesis of brain diseases.

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“…Recently, it has been hypothesized that dysregulated proliferation of microglia plays a detrimental role on neuronal cell viability, as shown in the case of experimental models of neurodegenerative disorders, such as Alzheimer’s disease [ 7 – 9 ], amyotrophic lateral sclerosis [ 10 , 11 ], and Huntington’s disease [ 12 ], as well as acute CNS injuries [ 13 , 14 ]. M1-activating stimuli were demonstrated to induce microglia proliferation [ 15 , 16 ], while the ability of microglia to proliferate in response to M2 signals has not been addressed yet. On the contrary, IL-4 has been recently shown to induce peripheral macrophage proliferation [ 17 ]; moreover, brain IL-4 levels may increase during pathological events, while administration of this molecule associates with beneficial effects on neuronal survival [ 18 – 21 ]; thus, promoting proliferation of microglia endowed with pro-resolving properties may have beneficial effects on disease progression and offer new therapeutic strategies to selectively modulate disease outcome.…”

Section: Introductionmentioning

confidence: 99%

Selective proliferative response of microglia to alternative polarization signals

Pepe

Maglie

Minoli

et al. 2017

J Neuroinflammation

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BackgroundMicroglia are resident myeloid cells of the central nervous system (CNS) that are maintained by self-renewal and actively participate in tissue homeostasis and immune defense. Under the influence of endogenous or pathological signals, microglia undertake biochemical transformations that are schematically classified as the pro-inflammatory M1 phenotype and the alternatively activated M2 state. Dysregulated proliferation of M1-activated microglia has detrimental effects, while an increased number of microglia with the alternative, pro-resolving phenotype might be beneficial in brain pathologies; however, the proliferative response of microglia to M2 signals is not yet known. We thus evaluated the ability of interleukin-4 (IL-4), a typical M2 and proliferative signal for peripheral macrophages, to induce microglia proliferation and compared it with other proliferative and M2 polarizing stimuli for macrophages, namely colony-stimulating factor-1 (CSF-1) and the estrogen hormone, 17β-estradiol (E2).MethodsRecombinant IL-4 was delivered to the brain of adult mice by intracerebroventricular (i.c.v.) injection; whole brain areas or ex vivo-sorted microglia were analyzed by real-time PCR for assessing the mRNA levels of genes related with cell proliferation (Ki67, CDK-1, and CcnB2) and M2 polarization (Arg1, Fizz1, Ym-1) or by FACS analyses of in vivo BrdU incorporation in microglia. Primary cultures of microglia and astrocytes were also tested for proliferative effects.ResultsOur results show that IL-4 only slightly modified the expression of cell cycle-related genes in some brain areas but not in microglia, where it strongly enhanced M2 gene expression; on the contrary, brain delivery of CSF-1 triggered proliferation as well as M2 polarization of microglia both in vivo and in vitro. Similar to IL-4, the systemic E2 administration failed to induce microglia proliferation while it increased M2 gene expression.ConclusionsOur data show that, in contrast to the wider responsiveness of peripheral macrophages, microglia proliferation is stimulated by selected M2 polarizing stimuli suggesting a role for the local microenvironment and developmental origin of tissue macrophages in regulating self-renewal following alternative activating stimuli.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1011-6) contains supplementary material, which is available to authorized users.

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Robust increase of microglia proliferation in the fornix of hippocampal axonal pathway after a single LPS stimulation

Cited by 35 publications

References 44 publications

Inhibition of semicarbazide‐sensitive amine oxidase/vascular adhesion protein‐1 reduces lipopolysaccharide‐induced neuroinflammation

Inhibition of semicarbazide‐sensitive amine oxidase/vascular adhesion protein‐1 reduces lipopolysaccharide‐induced neuroinflammation

Brain Region-dependent Heterogeneity and Dose-dependent Difference in Transient Microglia Population Increase during Lipopolysaccharide-induced Inflammation

Selective proliferative response of microglia to alternative polarization signals

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