FGF-2 released from degenerating neurons exerts microglial-induced neuroprotection via FGFR3-ERK signaling pathway

Abstract

BackgroundThe accumulation of activated microglia is a hallmark of various neurodegenerative diseases. Microglia may have both protective and toxic effects on neurons through the production of various soluble factors, such as chemokines. Indeed, various chemokines mediate the rapid and accurate migration of microglia to lesions. In the zebra fish, another well-known cellular migrating factor is fibroblast growth factor-2 (FGF-2). Although FGF-2 does exist in the mammalian central nervous system (CNS), it is unclear whether FGF-2 influences microglial function.MethodsThe extent of FGF-2 release was determined by ELISA, and the expression of its receptors was examined by immunocytochemistry. The effect of several drug treatments on a neuron and microglia co-culture system was estimated by immunocytochemistry, and the neuronal survival rate was quantified. Microglial phagocytosis was evaluated by immunocytochemistry and quantification, and microglial migration was estimated by fluorescence-activated cell sorting (FACS). Molecular biological analyses, such as Western blotting and promoter assay, were performed to clarify the FGF-2 downstream signaling pathway in microglia.ResultsFibroblast growth factor-2 is secreted by neurons when damaged by glutamate or oligomeric amyloid β 1-42. FGF-2 enhances microglial migration and phagocytosis of neuronal debris, and is neuroprotective against glutamate toxicity through FGFR3-extracellular signal-regulated kinase (ERK) signaling pathway, which is directly controlled by Wnt signaling in microglia.ConclusionsFGF-2 secreted from degenerating neurons may act as a ‘help-me’ signal toward microglia by inducing migration and phagocytosis of unwanted debris.

Expression and localization of Inter-alpha Inhibitors in rodent brain

“…Thus, taken together with our in vitro findings, IAIPs expression in different brain regions and cell types in vivo suggest the potential for diverse functions in healthy brain and potentially in neonatal related brain disorders. Moreover, our recent finding that exogenous blood derived IAIPs have important neuroprotective effects (Threlkeld et al, 2014, Gaudet et al, 2016) would appear to suggest that endogenous IAIPs could also exert neuroprotective effects analogous to other previously reported neuroprotective factors such as FGF-2 (Nozaki et al, 1993, Noda et al, 2014). …”

Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery

“…Emerging data now appears to recast some of these extracellular factors as neuronal “help-me” signals (Kyritsis et al 2012; Mizuno et al 2011; Noda et al 2011; Noda et al 2014; Xing et al 2014). After brain injury, neurons can release unique “help-me” signals, including chemokines, cytokines, growth factors etc, which will interact with receptors expressed in microglia to guide microglial activation into a beneficial phenotype of neuroprotection and neurorecovery (Figure 3) .…”

“…Here, instead of discussing the well-known effects of FGF2 on neuroprotection, neurogenesis and angiogenesis, we will focus on the novel role of FGF2 as a candidate neuronal help-me signal. Basically, FGF2 can be released from damaged neurons, and mediates crosstalk between degenerating neurons and microglia (Figueiredo et al 2008; Noda et al 2014). …”

“…In another study, damaged neurons rapidly released neuroprotective levels of FGF2 that also augmented microglial migration via FGFR3-Wnt-ERK signaling (Noda et al 2014). Neurons comprise the major source of stimulated FGF2 release (Noda et al 2014).…”

Dysregulated fibroblast growth factor (FGF) signaling in neurological and psychiatric disorders

“…Intrastriatal expression of LMW FGF2 has also been shown to increase dopaminergic neuron recovery following a chemically induced lesion [60]. This increased survival is thought to be the result of signaling through microglia to clean up amyloid β [61]. In the context of genetic models, mice deficient in all FGF2 isoforms show reduced dopamine (DA) neuron number.…”