The neural cell adhesion molecule-derived peptide, FGL, attenuates lipopolysaccharide-induced changes in glia in a CD200-dependent manner

Abstract

Please cite this article as: F. Fionnuala Cox, V. Berezin, E. Bock, M.A. Lynch, The neural cell adhesion moleculederived peptide, FGL, attenuates lipopolysaccharide-induced changes in glia in a CD200-dependent manner, Neuroscience (2013), doi: http://dx.doi.org/10.1016/j.neuroscience. 2012.12.030 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACT Fibroblast growth loop (FGL) is a neural cell adhesion molecule (NCAM)-mimetic peptide that mimics the interaction of NCAM with fibroblast growth factor receptor (FGFR). FGLincreases neurite outgrowth and promotes neuronal survival in vitro, and it has also been shown to have neuroprotective effects in vivo. More recent evidence has indicated that FGL has anti-inflammatory effects, decreasing age-related changes in microglial activation and production of inflammatory cytokines. These changes have been associated with an FGLinduced increase in expression of the glycoprotein, CD200, which interacts with its receptor to help maintain microglia in a quiescent state. However whether the FGL-induced antiinflammatory effects are CD200-dependent has not been examined. The objective of this study was to address this question. Mixed glia were prepared from brain tissue of neonatal wildtype and CD200-deficient mice and preincubated with FGL prior to stimulation with lipopolysaccharide (LPS). Cells were assessed for mRNA expression of markers of microglial activation, CD11b, CD40 and intercellular adhesion molecule 1 (ICAM) and also the inflammatory cytokines, interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α, while supernatant concentrations of these cytokine were also assessed. LPS significantly increased all these parameters and the effect was greater in cells prepared from CD200-deficient mice. Whereas FGL attenuated the LPS-induced changes in cells from wildtype mice, it did not do so in cells from CD200-deficient mice. We conclude that the FGL-induced changes in microglial activation are CD200-dependent and demonstrate that the interaction of astrocytes with microglia is critically important for modulating microglial activation.

Selection and Prioritization of Candidate Drug Targets for Amyotrophic Lateral Sclerosis Through a Meta-Analysis Approach

“…5). Similarly, functional FGFR peptide agonists (e.g., FG Loop (FGL) peptide) seem to be of therapeutic interest for ALS due to their effects not only on neurogenesis but also on synaptic formation, neuron–glia interactions, and inflammation (Woodbury and Ikezu 2014; Ohta et al 2006; Li et al 2010; Cox et al 2013). Further studies are needed to better clarify the involvement of FGF/FGFR signaling in ALS pathophysiology and its role as a future therapeutic target for ALS (Fig.…”

Fibroblast Growth Factor-2 Signaling in Neurogenesis and Neurodegeneration

“…Interestingly, FGL’s anti-inflammatory effects are associated with increased expression of the neuronal glycoprotein CD200 by astrocytes [72] and neurons [73] and have subsequently been found to be dependent on CD200 expression [73]. CD200 is known to play a role in maintaining microglia in a non-inflammatory (“quiescent”) state, which has been suggested to protect synaptic function in the aging brain [74].…”

“…2) [80]. Interestingly, Cox et al (2013) recently demonstrated FGL-induced, CD200-dependent attenuation of LPS-induced changes in microglial pro-inflammatory activation [73], suggesting that the earlier findings of Downer et al (2010) may correspond to attenuation of a pro-inflammatory phenotype of microglial activation.…”

How dependent is synaptic plasticity on microglial phenotype?

“…It has been shown that conditioned medium obtained from astrocytes decreased hydrogen peroxide (H 2 O 2 )-induced reactive oxygen species (ROS) production, increased expression and activity of the antioxidant enzyme, haemoxygenase-1, and decreased IFN-induced inducible iNOS expression in microglia (Min et al, 2006). Astrocytes also modulate microglial activation by virtue of the fact that they express CD200 (Cox et al, 2013); indeed incubation of microglia with CD200-bearing astrocytic membrane preparations attenuates the LPS-induced increase in mRNA expression of IL-1, TNF and IL-6 and the LPS-induced release of TNF and IL-6 (Cox et al, 2013).…”