Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression.
Glutamate-induced excito-neurotoxicity likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases. Microglial clearance of dying neurons and associated debris is essential to maintain healthy neural networks in the central nervous system. In fact, the functions of microglia are regulated by various signaling molecules that are produced as neurons degenerate. Here, we show that the soluble CX3C chemokine fractalkine (sFKN), which is secreted from neurons that have been damaged by glutamate, promotes microglial phagocytosis of neuronal debris through release of milk fat globule-EGF factor 8, a mediator of apoptotic cell clearance. In addition, sFKN induces the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in microglia in the absence of neurotoxic molecule production, including NO, TNF, and glutamate. sFKN treatment of primary neuron-microglia co-cultures significantly attenuated glutamate-induced neuronal cell death. Using several specific MAPK inhibitors, we found that sFKN-induced heme oxygenase-1 expression was primarily mediated by activation of JNK and nuclear factor erythroid 2-related factor 2. These results suggest that sFKN secreted from glutamate-damaged neurons provides both phagocytotic and neuroprotective signals.
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Mariko
M
Noda
Yukiko
Y
Doi
Jianfeng
J
Liang
Jun
J
Kawanokuchi
Yoshifumi
Y
Sonobe
Hideyuki
H
Takeuchi
Tetsuya
T
Mizuno
Akio
A
Suzumura
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D018920:Coculture Techniques; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018698:Glutamic Acid / Q000009:adverse effects / Q000494:pharmacology; D051547:Heme Oxygenase-1; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000954:Antigens, Surface; D000975:Antioxidants; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; D008565:Membrane Proteins; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D018698:Glutamic Acid; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4