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Published on: March 31, 2015
miR-155 Is Essential for Inflammation-Induced Hippocampal Neurogenic Dysfunction
Maya E Woodbury1, Robert W Freilich2, Christopher J Cheng3
1Department of Pharmacology and Experimental Therapeutics and Graduate Program in Neuroscience, Boston University, Boston, Massachusetts 02118, and.
Abstract:
Peripheral and CNS inflammation leads to aberrations in developmental and postnatal neurogenesis, yet little is known about the mechanism linking inflammation to neurogenic abnormalities. Specific miRs regulate peripheral and CNS inflammatory responses. miR-155 is the most significantly upregulated miR in primary murine microglia stimulated with lipopolysaccharide (LPS), a proinflammatory Toll-Like Receptor 4 ligand. Here, we demonstrate that miR-155 is essential for robust IL6 gene induction in microglia under LPS stimulation in vitro. LPS-stimulated microglia enhance astrogliogenesis of cocultured neural stem cells (NSCs), whereas blockade of IL6 or genetic ablation of microglial miR-155 restores neural differentiation. miR-155 knock-out mice show reversal of LPS-induced neurogenic deficits and microglial activation in vivo. Moreover, mice with transgenic elevated expression of miR-155 in nestin-positive neural and hematopoietic stem cells, including microglia, show increased cell proliferation and ectopically localized doublecortin-positive immature neurons and radial glia-like cells in the hippocampal dentate gyrus (DG) granular cell layer. Microglia have proliferative and neurogenic effects on NSCs, which are significantly altered by microglial miR-155 overexpression. In addition, miR-155 elevation leads to increased microglial numbers and amoeboid morphology in the DG. Our study demonstrates that miR-155 is essential for inflammation-induced neurogenic deficits via microglial activation and induction of IL6 and is sufficient for disrupting normal hippocampal development.
Insights
MicroRNA-155 (miR-155) drives inflammation-induced neurogenesis deficits by activating microglia and inducing IL6. Inhibiting miR-155 or IL6 restores normal neural development.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Inflammation impacts neurogenesis, but mechanisms are unclear.
- MicroRNAs (miRs) regulate inflammatory and neural processes.
- miR-155 is upregulated in microglia during inflammation.
Purpose of the Study:
- Investigate miR-155's role in inflammation-induced neurogenesis deficits.
- Elucidate miR-155's mechanism in microglial activation and IL6 induction.
- Determine miR-155's sufficiency in disrupting hippocampal development.
Main Methods:
- In vitro studies using lipopolysaccharide (LPS)-stimulated microglia and neural stem cells (NSCs).
- Genetic manipulation: miR-155 knockout mice and transgenic mice with elevated miR-155.
- In vivo assessments of neurogenesis, microglial activation, and hippocampal morphology.
Main Results:
- miR-155 is crucial for LPS-induced IL6 production in microglia.
- Microglial activation and IL6 mediate inflammation-induced neurogenic deficits.
- miR-155 knockout reversed LPS-induced neurogenic deficits and microglial activation.
- Elevated miR-155 in stem cells disrupted hippocampal development, increasing proliferation and causing ectopic neuron/glia localization.
Conclusions:
- miR-155 is essential for inflammation-induced neurogenic deficits via microglial IL6 induction.
- miR-155 dysregulation is sufficient to disrupt normal hippocampal development.
- Targeting miR-155 may offer therapeutic potential for neuroinflammatory conditions.
