Dataset Information

Regulatory Control of Microglial Phagocytosis by Estradiol and Prostaglandin E2 in the Developing Rat Cerebellum.

ABSTRACT: Microglia are essential to sculpting the developing brain, and they achieve this in part through the process of phagocytosis which is regulated by microenvironmental signals associated with cell death and synaptic connectivity. In the rat cerebellum, microglial phagocytosis reaches its highest activity during the third postnatal week of development but the factors regulating this activity are unknown. A signaling pathway, involving prostaglandin E2 (PGE2) stimulation of the estrogen synthetic enzyme aromatase, peaks during the 2nd postnatal week and is a critical regulator of Purkinje cell maturation. We explored the relationship between the PGE2-estradiol pathway and microglia in the maturing cerebellum. Toward that end, we treated developing rat pups with pharmacological inhibitors of estradiol and PGE2 synthesis and then stained microglia with the universal marker Iba1 and quantified microglia engaged in phagocytosis as well as phagocytic cups in the vermis and cerebellar hemispheres. Inhibition of aromatase reduced the number of phagocytic cups in the vermis, but not in the cerebellar hemisphere at postnatal day 17. Similar results were found after treatment with nimesulide and indomethacin, inhibitors of the PGE2-producing enzymes cyclooxygenase 1 and 2. In contrast, treatment with estradiol or PGE2 had little effect on microglial phagocytosis in the developing cerebellum. Thus, endogenous estrogens and prostaglandins upregulate the phagocytic activity of microglia during a select window of postnatal cerebellar development, but exogenous treatment with these same signaling molecules does not further increase the already high levels of phagocytosis. This may be due to an upper threshold or evidence of resistance to exogenous perturbation.

SUBMITTER: Perez-Pouchoulen M

PROVIDER: S-EPMC6763383 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Regulatory Control of Microglial Phagocytosis by Estradiol and Prostaglandin E2 in the Developing Rat Cerebellum.

Perez-Pouchoulen Miguel M Yu Stacey J SJ Roby Clinton R CR Bonsavage Nicole N McCarthy Margaret M MM

Cerebellum (London, England) 20191001 5

Microglia are essential to sculpting the developing brain, and they achieve this in part through the process of phagocytosis which is regulated by microenvironmental signals associated with cell death and synaptic connectivity. In the rat cerebellum, microglial phagocytosis reaches its highest activity during the third postnatal week of development but the factors regulating this activity are unknown. A signaling pathway, involving prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) stimulation of the ...[more]

PMID: 31435854

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Project description:Prostaglandins (PGs) are ubiquitous membrane-derived, lipid-signaling molecules with wide ranging effects throughout the body. In the brain, PGE(2) is the key regulator of fever after inflammation but is also implicated in neural development and synaptic plasticity. The steroid hormone estradiol is also a key regulator of neural development and synaptic plasticity. Recently, we showed that administering cyclooxygenase (COX) inhibitors to block PGE(2) production increased the total length of Purkinje cell dendrites, the number of dendritic spines, and the level of spinophilin protein, which is enriched in dendritic spines. Correspondingly, PGE(2) administration into the cerebellum decreased spinophilin protein content. We now report that PGE(2) stimulates estradiol synthesis in the immature rat cerebellum via enhanced activity of the aromatase enzyme. Treatment with cyclooxygenase inhibitors reduced cerebellar aromatase activity and estradiol content whereas PGE(2) administration increased both. Treatment with either PGE(2) or estradiol stunted Purkinje neuron dendritic length and complexity and produced a corresponding reduction in spinophilin content. Treatment with formestane to inhibit aromatase activity led to excessive sprouting of the dendritic tree, whereas elevated estradiol had the opposite effect. Electrophysiological measurements from Purkinje neurons revealed novel sex differences in input resistance and membrane capacitance that were abolished by estradiol exposure, whereas a sex difference in the amplitude of the afterhyperpolarization after an action potential was not. Correlated changes in action potential threshold suggest that prolonged alterations in neuronal firing activity could be a consequence of increased estradiol content during the second week of life. These findings reveal a previously unappreciated role for PG-stimulated steroidogenesis in the developing brain and a new potential route for inflammation-mediated disruption of neuronal maturation.

Project description:BACKGROUND: Nicotinic acetylcholine (Ach) receptors are ligand-gated pentameric ion channels whose main function is to transmit signals for the neurotransmitter Ach in peripheral and central nervous system. However, the alpha7 nicotinic receptor has been recently found in several non-neuronal cells and described as an important regulator of cellular function. Nicotine and ACh have been recently reported to inhibit tumor necrosis factor-alpha (TNF-alpha) production in human macrophages as well as in mouse microglial cultures. In the present study, we investigated whether the stimulation of alpha7 nicotinic receptor by the specific agonist nicotine could affect the functional state of activated microglia by promoting and/or inhibiting the release of other important pro-inflammatory and lipid mediator such as prostaglandin E2. METHODS: Expression of alpha7 nicotinic receptor in rat microglial cell was examined by RT-PCR, immunofluorescence staining and Western blot. The functional effects of alpha7 receptor activation were analyzed in resting or lipopolysaccharide (LPS) stimulated microglial cells pre-treated with nicotine. Culture media were assayed for the levels of tumor necrosis factor, interleukin-1beta, nitric oxide, interleukin-10 and prostaglandin E2. Total RNA was assayed by RT-PCR for the expression of COX-2 mRNA. RESULTS: Rat microglial cells express alpha7 nicotinic receptor, and its activation by nicotine dose-dependently reduces the LPS-induced release of TNF-alpha, but has little or no effect on nitric oxide, interleukin-10 and interleukin-1beta. By contrast, nicotine enhances the expression of cyclooxygenase-2 and the synthesis of one of its major products, prostaglandin E2. CONCLUSIONS: Since prostaglandin E2 modulates several macrophage and lymphocyte functions, which are instrumental for inflammatory resolution, our study further supports the existence of a brain cholinergic anti-inflammatory pathway mediated by alpha7 nicotinic receptor that could be potentially exploited for novel treatments of several neuropathologies in which local inflammation, sustained by activated microglia, plays a crucial role.

Dataset Information

Regulatory Control of Microglial Phagocytosis by Estradiol and Prostaglandin E2 in the Developing Rat Cerebellum.

Publications

Regulatory Control of Microglial Phagocytosis by Estradiol and Prostaglandin E2 in the Developing Rat Cerebellum.

Similar Datasets

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