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An In Vitro Model for the Study of Cellular Pathophysiology in Globoid Cell Leukodystrophy
Published on: October 21, 2014
Lipopolysaccharide-activated microglia induce death of oligodendrocyte progenitor cells and impede their development
1Department of Pediatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Insights
Activated microglia damage oligodendrocyte progenitor cells (OPCs) through nitric oxide and cytokines, impairing myelin basic protein (MBP) production and causing cell death in periventricular leukomalacia (PVL). Reduced trophic factors also contribute to OL death.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Periventricular leukomalacia (PVL) involves oligodendrocyte (OL) progenitor cell (OPC) damage and hypomyelination, common in premature infants.
- Maternal infection/inflammation is linked to PVL, with activated microglia implicated but mechanisms unclear.
Purpose of the Study:
- To elucidate the mechanisms by which lipopolysaccharide (LPS)-activated microglia affect OPC survival and development.
- To identify specific pathways and molecules involved in microglial-induced OPC damage.
Main Methods:
- Utilized LPS-activated microglia and OPC co-culture models.
- Investigated time-dependent cell death mechanisms using inhibitors (l-NAME, anti-TNF-alpha, anti-proNGF).
- Assessed the role of neurotrophic factors (IGF-1, CNTF) and their suppression by LPS.
Main Results:
- LPS-activated microglia impede OL lineage progression, reduce myelin basic protein (MBP) production, and cause OPC death.
- Two distinct cell death phases were observed: early NO-dependent oxidative damage and delayed cytokine-mediated (TNF-alpha, proNGF) death.
- Microglia-derived IGF-1 and CNTF were suppressed, and their exogenous administration protected OLs.
Conclusions:
- Activated microglia induce time-dependent, multi-mechanism OPC death and impair OL development, contributing to PVL pathogenesis.
- Nitric oxide, TNF-alpha, proNGF, and reduced trophic support are key mediators of microglial-induced white matter damage.
- Findings offer insights into PVL mechanisms and potential therapeutic targets.
Abstract:
Damage to oligodendrocyte (OL) progenitor cells (OPCs) and hypomyelination are two hallmark features of periventricular leukomalacia (PVL), the most common form of brain damage in premature infants. Clinical and animal studies have linked the incidence of PVL to maternal infection/inflammation, and activated microglia have been proposed to play a central role. However, the precise mechanism of how activated microglia adversely affects the survival and development of OPCs is still not clear. Here we demonstrate that lipopolysaccharide (LPS)-activated microglia are deleterious to OPCs, that is, impeding OL lineage progression, reducing the production of myelin basic protein (MBP), and mediating OPC death. We further demonstrate that LPS-activated microglia mediate OPC death by two distinct mechanisms in a time-dependent manner. The early phase of cell damage occurs within 24 h after LPS treatment, which is mediated by nitric oxide (NO)-dependent oxidative damage and is prevented by N(G)-nitro-l-arginine methyl ester (l-NAME), a general inhibitor of nitric oxide synthase. The delayed cell death is evident at 48 h after LPS treatment, is mediated by cytokines, and is prevented by blocking the activity of tumor necrosis factor-alpha (TNF-alpha) and pro-nerve growth factor (proNGF), but not by l-NAME. Furthermore, microglia-derived insulin-like growth factor-1 (IGF-1) and ciliary neurotrophic factor (CNTF) were significantly suppressed by LPS, and exogenous IGF-1 and CNTF synergistically protected OLs from death induced by LPS-treated microglia conditioned medium, indicating that a deficiency in trophic support may also be involved in OL death. Our finding that LPS-activated microglia not only induce two waves of cell death but also greatly impair OL development may shed some light on the mechanisms underlying selective white matter damage and hypomyelination in PVL.
