Neuron-microglia crosstalk up-regulates neuronal FGF-2 expression which mediates neuroprotection against excitotoxicity via JNK1/2

Catarina Figueiredo, Teresa F. Pais, João R. Gomes, Sukalyan Chatterjee

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)73-85
Number of pages13
JournalJournal of Neurochemistry
Volume107
Issue number1
DOIs
Publication statusPublished - Oct 2008
Externally publishedYes

Keywords

  • Cathepsins
  • Fibroblast growth factor receptor
  • Fibroblast growth factor-2
  • Heat-shock protein induction
  • Mitogen-activated protein kinases
  • Neuron-microglia crosstalk
  • Neuroprotection

Fingerprint

Dive into the research topics of 'Neuron-microglia crosstalk up-regulates neuronal FGF-2 expression which mediates neuroprotection against excitotoxicity via JNK1/2'. Together they form a unique fingerprint.

Cite this