Activated glia induce neuron death via MAP kinase signaling pathways involving JNK and p38

Abstract

Chronic glial activation in neurodegenerative diseases contributes to neuronal dysfunction and neuron loss through production of neuroinflammatory molecules. However, the molecular mechanisms, particularly the signal transduction pathways involved in glia-dependent neuron death, are poorly understood. As a first step to address this question, we used a neuron-glia co-culture system that allows diffusion of soluble molecules between glia and neurons to test the potential importance of mitogen-activated protein kinase (MAPK) signaling pathways in the glia-induced neuron death. Activation of glia in co-culture by lipopolysaccharide (LPS) induced apoptotic-like neuron death. The MAPKs tested (p38, JNK, ERK1/2) were activated in both glia and neurons following LPS treatment, suggesting their involvement in both glial activation and neuronal response to diffusible, glia-derived neurotoxic molecules. Inhibitors of p38 and JNK partially blocked neuron death in the LPS-treated co-culture, whereas an ERK1/2 pathway inhibitor did not protect neurons. These results show that p38 and JNK MAPKs, but not ERK1/2 MAPK, are important signal transduction pathways contributing to glia-induced neuron death.

Thrombin induces neurodegeneration and microglial activation in the cortex in vivo and in vitro: Proteolytic and non-proteolytic actions

“…Increasing evidence suggests that activated microglia contribute to neuronal cell death [8][9][10][11]. For example, we [6] and Carreno-Muller et al [12] demonstrated that thrombin can cause the death of nigral dopaminergic neurons by activating microglia to produce pro-inflammatory cytokines and cytotoxic molecules.…”

Microglia Overexpressing the Macrophage Colony-Stimulating Factor Receptor Are Neuroprotective in a Microglial-Hippocampal Organotypic Coculture System

“…It is curious that LPS pretreatment of BV-2 microglia did not enhance NMDA neuronal toxicity, because LPS-activated microglia when cocultured with monotypic neurons can result in neurotoxicity (Xie et al, 2004). Aschner et al (1999) suggested that neurons in dissociated cultures are particularly susceptible to negative effects of microglia as a result of the absence of normal neuronal-glial interactions.…”

“…Transfection efficiency is ϳ90% (data not shown). To compare the effects of c-fms transfection with that of endotoxin, a classical stimulus for microglial activation that can induce microglial injury to monotypic neuronal cultures (Kim and Ko, 1998;Wang et al, 2002;Xie et al, 2004), some BV-2 cells were treated with 5 g/ml LPS (Sigma, St. Louis, MO). After 24 h of transfection or LPS treatment, cells were detached from the wells by mechanical pipetting, quantified, and used for assembly of the organotypic coculture.…”

“…Increased microglial M-CSFR expression has been linked to CP neurotoxicity (Hao et al, 2002). Because the endotoxin lipopolysaccharide (LPS) has been used to stimulate microglial activation and microglial-induced neurotoxicity (Kim and Ko, 1998;Wang et al, 2002;Xie et al, 2004), we compared the effect of microglia overexpressing the M-CSFR on neuronal survival to that of microglia treated with LPS.…”

c-Jun N-Terminal Kinase Activation Responses Induced by Hippocampal Kindling Are Mediated by Reactive Astrocytes

“…Indeed, there is accumulating evidence that MAP kinase activation mediates astroglial production of a host of inflammatory mediators under these conditions, which contribute to neuronal death (Migheli et al, 1997;Falsig et al, 2004). Using a special neuronglia coculture system, Xie et al (2004) demonstrated recently that lipopolysaccharide-induced activation in glia triggers neuronal death. The authors postulated that JNK activation may be part of a glial signaling pathway that leads to the release of diffusible neurotoxic molecules such as NO.…”