title: Neuron-microglia crosstalk up-regulates neuronal FGF-2 expression which mediates neuroprotection against excitotoxicity via JNK1/2.
abstract: Glial cells and neurons are in constant reciprocal signalling both under physiological and neuropathological conditions. Microglial activation is often associated with neuronal death during inflammation of the CNS, although microglial cells are also known to exert a neuroprotective role. In this work, we investigated the interplay between cerebellar granule neurons (CGN) and microglia in the perspective of CGN survival to an excitotoxic stimulus, quinolinic acid (QA), a catabolite of the tryptophan degradation pathway. We observed that CGN succumb to QA challenge via extracellular signal regulated kinase 1 and 2 (ERK) activation. Our data with transgenic mice expressing the natural inhibitor of calpains, calpastatin, indicate that together with cathepsins they mediate QA-induced toxicity acting downstream of the mitogen-activated protein kinase kinase-ERK pathway. Microglial cells are not only resistant to QA but can rescue neurons from QA-mediated toxicity when they are mixed in culture with neurons or by using mixed culture-conditioned medium (MCCM). This effect is mediated via fibroblast growth factor-2 (FGF-2) present in MCCM. FGF-2 is transcriptionally up-regulated in neurons and secreted in the MCCM as a result of neuron-microglia crosstalk. The neuroprotection is associated with the retention of cathepsins in the lysosomes and with transactivation of inducible heat-shock protein 70 downstream of FGF-2. Furthermore, FGF-2 upon release by neurons activates c-jun N-terminal kinase 1 and 2 pathway which also contributes to neuronal survival. We suggest that FGF-2 plays a pivotal role in neuroprotection against QA as an outcome of neuron-microglia interaction.
authors.affiliation: Centro Biologia Desenvolvimento, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Figueiredo
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Pais
authors.forename: João R
authors.initials: JR
authors.lastname: Gomes
authors.forename: Sukalyan
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000378:metabolism / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D009924:Organ Culture Techniques; D017378:Quinolinic Acid / Q000378:metabolism / Q000633:toxicity; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D002135:Calcium-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D009498:Neurotoxins; D016222:Fibroblast Growth Factor 2; C033668:calpastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D002403:Cathepsins; D017378:Quinolinic Acid