Elsevier

Neuroscience

Volume 166, Issue 2, 17 March 2010, Pages 464-475
Neuroscience

Cellular Neuroscience
Research Paper
Lipopolysaccharide-activated microglia induce death of oligodendrocyte progenitor cells and impede their development

https://doi.org/10.1016/j.neuroscience.2009.12.040Get rights and content

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 NG-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-α) 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.

Section snippets

Chemicals

LPS (055:B5) and NG-nitro-l-arginine methyl ester (l-NAME) were purchased from Sigma (St. Louis, MO, USA). Dulbecco's Modified Eagle Medium (DMEM)/Ham's F12 and F15 medium, insulin-transferrin-selenium, bovine serum albumin (BSA), penicillin/streptomycin, 2.5% trypsin, and carboxy-H2DCFDA were purchased from Invitrogen (Carlsbad, CA, USA). 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) kit and lactate dehydrogenase (LDH) kit were purchased from

LPS-activated microglia-induced acute OPC death was associated with NO

To investigate the interaction between OPCs and microglia after LPS exposure, we first used a microglia-OPC co-culture system that physically separates microglia and OPCs but allows free exchange of molecules between the two culture compartments. As shown in Fig. 1 A and 1 B, no cell death was detected in the control culture over the 48 h period. However, a large amount of OPCs directly underneath the cell culture insert (Fig. 1A: LPS center, also shown in lower magnification in Fig. 1B) died

Discussion

Here we provide evidence that LPS-activated microglia are harmful to OPC. This finding is consistent with many studies showing that activated microglia were deleterious to developing OLs (Pang et al., 2000, Sherwin and Fern, 2005, Domercq et al., 2007, Li et al., 2005). The novel finding of the current study, however, is that we demonstrated that OPC died in two distinct time frames.

Activated microglia rapidly respond as the first line of defense to protect against brain damage. During

Conclusion

This study provides new insight into the mechanisms of OL damage by showing a dynamic OPC death mediated by LPS-activated microglia. Further, the deficiency in trophic support by LPS-activated microglia may contribute to the decrease in OL development.

Acknowledgments

This work was supported partially by HD 35496 from National Institute of Child Health and Human Development; NS 54278 from National Institute of Neurological Disorders and Stroke; and by funds from Newborn Medicine and the Department of Pediatrics, University of Mississippi Medical Center.

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