Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10

Almolda, Beatriz; Labra, Carmen de; Barrera, Iliana; Gruart, Agnès; Delgado‐García, José M.; Villacampa, Nàdia; Vilella, Antonietta; Höfer, Markus; Hidalgo, Juan; Campbell, Iain L.; González, Berta; Castellano, Bernardo

doi:10.1016/j.bbi.2014.10.015

Cited by 51 publications

(47 citation statements)

References 82 publications

(104 reference statements)

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“…For instance, IL‐1β is not only a prototypic inflammatory cytokine, but it can increase the phosphorylation of the NMDA receptor NR2B subunit resulting in increased neuronal excitability (Balosso et al, ). Similarly, the anti‐inflammatory cytokine IL‐10 is capable of rapidly regulating GABAergic transmission in dentate gyrus neurons by lowering excitability and changing LTP responses (Almolda et al, ; Suryanarayanan et al, ). Several interleukins can also be produced by astrocytes, by neurons, or by leukocytes that can be driven in the brain by specific chemokines.…”

Section: Discussionmentioning

confidence: 99%

Time Course of Blood and Brain Cytokine/Chemokine Levels Following Adolescent Alcohol Exposure and Withdrawal in Rats

Sanchez‐Alavez

Nguyen

Mori

et al. 2019

Alcoholism Clin & Exp Res

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Background: Adolescence is a critical period for neural development, and alcohol exposure during adolescence can lead to an elevated risk for health consequences as well as alcohol use disorders. Clinical and experimental data suggest that chronic alcohol exposure may produce immunomodulatory effects that can lead to the activation of pro-inflammatory cytokine pathways as well as microglial markers. The present study evaluated, in brain and blood, the effects of adolescent alcohol exposure and withdrawal on microglia and on the most representative pro-and anti-inflammatory cytokines and major chemokines that can contribute to the establishing of a neuroinflammatory environment.Methods: Wistar rats (males, n = 96) were exposed to ethanol (EtOH) vapors, or air control, for 5 weeks over adolescence (PD22-PD58). Brains and blood samples were collected at 3 time points: (i) after 35 days of vapor/air exposure (PD58); (ii) after 1 day of withdrawal (PD59), and (iii) 28 days after withdrawal (PD86). The ionized calcium-binding adapter molecule 1 (Iba-1) was used to index microglial activation, and cytokine/chemokine responses were analyzed using magnetic bead panels.Results: After 35 days of adolescent vapor exposure, a significant increase in Iba-1 immunoreactivity was seen in amygdala, frontal cortex, hippocampus, and substantia nigra. However, Iba-1 density returned to control levels at both 1 day and 28 days of withdrawal except in the hippocampus where Iba-1 density was significantly lower than controls. In serum, adolescent EtOH exposure induced a reduction in IL-13 and an increase in fractalkine at day 35. After 1 day of withdrawal, IL-18 was reduced, and IP-10 was elevated, whereas both IP-10 and IL-10 were elevated at 28 days following withdrawal. In the frontal cortex, adolescent EtOH exposure induced an increase in IL-1b at day 35, and 28 days of withdrawal, and IL-10 was increased after 28 days of withdrawal.Conclusion: These data demonstrate that EtOH exposure during adolescence produces significant microglial activation; however, inflammatory markers seen in the blood appear to differ from those observed in the brain.

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Section: Discussionmentioning

confidence: 99%

Time Course of Blood and Brain Cytokine/Chemokine Levels Following Adolescent Alcohol Exposure and Withdrawal in Rats

Sanchez‐Alavez

Nguyen

Mori

et al. 2019

Alcoholism Clin & Exp Res

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“…Because astrocytes are a key source of IL-10 in the CNS [32], it is possible that targeting S1PR1 produces an anti-inflammatory shift in astrocytic phenotype in CIBP. Astrocyte-derived IL-10 plays a vital role in regulating microglial phenotype and neurotransmission in the hippocampus [2] and furthermore, astrocyte-derived IL-10 is reported to limit signaling-related neurotoxicity in vivo [61]. Therefore, it is possible that FTY720-mediated antinociception continuously elicits the production of glial IL-10 as a neuromodulator that reduces microglial activation and, critically, limits the extent of activation in the lumbar spinal cord ipsilateral to injury.…”

Section: Discussionmentioning

confidence: 99%

Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

Grenald

Doyle

Zhang

et al. 2017

Pain

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Metastatic bone pain is the single most common form of cancer pain and persists as a result of peripheral and central inflammatory, as well as neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced bone pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P). Intriguingly, de novo sphingolipid biosynthesis was increased as shown by the elevations of dihydro-ceramides and dihydro-S1P. We next identified the S1P receptor subtype 1 (S1PR1) as a novel target for therapeutic intervention. Intrathecal or systemic administration of the competitive and functional S1PR1 antagonists, TASP0277308 and FTY720/Fingolimod, respectively, attenuated cancer-induced spontaneous flinching and guarding. Inhibiting CIBP by systemic delivery of FTY720 did not result in antinociceptive tolerance over 7 days. FTY720 administration enhanced IL-10 in the lumbar ipsilateral spinal cord of CIBP animals and intrathecal injection of an IL-10 neutralizing antibody mitigated the ability of systemic FTY720 to reverse CIBP. FTY720 treatment was not associated with alterations in bone metabolism in vivo. Studies here identify a novel mechanism to inhibit bone cancer pain by blocking the actions of the bioactive metabolites S1P and dihydro-S1P in lumbar spinal cord induced by bone cancer and support potential fast-track clinical application of the FDA-approved drug, FTY720, as a therapeutic avenue for CIBP.

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“…Rather, interactions with other immune cells, including microglia, are likely necessary for this process. For example, astrocyte-derived IL-10 causes both altered microglia activation and impaired LTP (Almolda et al, 2015). Conversely, microglial activation can result in astrocyte-mediated modulation of synaptic function, resulting in rapid increases of astrocytic glutamate release (Pascual et al, 2012).…”

Section: Neuroimmune Modulation Of Memory: Avenues For Investigating mentioning

confidence: 99%

(Putative) sex differences in neuroimmune modulation of memory

Tronson

Collette

2016

J of Neuroscience Research

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The neuroimmune system is significantly sexually dimorphic, with sex differences evident in the number and activation states of microglia, in the activation of astrocytes, and in cytokine release and function. Neuroimmune cells and signaling are now recognized as critical for many neural functions throughout the lifespan, including synaptic plasticity and memory function. Here we address the question of how cytokines, astrocytes, and microglia contribute to memory, and specifically how neuroimmune modulation of memory differentially affects males and females. Understanding sex differences in both normal memory processes and dysregulation of memory in psychiatric and neurological disorders is critical for developing treatment and preventive strategies for memory disorders that are effective for both men and women.

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Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10

Cited by 51 publications

References 82 publications

Time Course of Blood and Brain Cytokine/Chemokine Levels Following Adolescent Alcohol Exposure and Withdrawal in Rats

Time Course of Blood and Brain Cytokine/Chemokine Levels Following Adolescent Alcohol Exposure and Withdrawal in Rats

Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

(Putative) sex differences in neuroimmune modulation of memory

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