Glial Cell Line-Derived Neurotrophic Factor Family Members Reduce Microglial Activation via Inhibiting p38MAPKs-Mediated Inflammatory Responses.

Uta Rickert,Steffen Grampp,Janka Held-Feindt,Jessica Spreu,Friederike Knerlich-Lukoschus,Ralph Lucius,Henrik Wilms

doi:10.1155/2014/369468

Abstract

Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF) family ligands (GFL) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson's disease. However, little is known about direct influences of the GFL on microglia function, which are known to express part of the GDNF receptor system. Using RT-PCR and immunohistochemistrym we investigated the expression of the GDNF family receptor alpha 1 (GFR alpha) and the coreceptor transmembrane receptor tyrosine kinase (RET) in rat microglia in vitro as well as the effect of GFL on the expression of proinflammatory molecules in LPS activated microglia. We could show that GFL are able to regulate microglia functions and suggest that part of the well known neuroprotective action may be related to the suppression of microglial activation. We further elucidated the functional significance and pathophysiological implications of these findings and demonstrate that microglia are target cells of members of the GFL (GDNF and the structurally related neurotrophic factors neurturin (NRTN), artemin (ARTN), and persephin (PSPN)).

Highlights

Microglia are distributed throughout the CNS as a network of resting immunocompetent cells derived from the monocyte/macrophage lineage
It was demonstrated that microglial inducible nitric oxide synthase as well as Interleukin-1 beta IL-6 (IL-1β) levels is increased in the brain of patients suffering from Parkinson’s disease (PD) [4], leading to the hypothesis that the increased levels of iNOS or IL-1β may contribute to the pathophysiology of neurodegenerative disorders, especially for PD [5]
To determine whether glial cell line-derived neurotrophic factor (GDNF) receptors are expressed on primary rat microglia, cells were analyzed by qualitative PCR for mRNA transcripts of GFRα1 and receptor tyrosine kinase (RET)

Summary

Introduction

Microglia are distributed throughout the CNS as a network of resting immunocompetent cells derived from the monocyte/macrophage lineage. By releasing various factors such as cytokines (i.e., interleukins: IL-1β, IL-6) or proinflammatory molecules (e.g., prostaglandins, proteolytic enzymes, reactive oxygen intermediates (ROI), or nitric oxide (NO)), [1,2,3] microglia are able to damage CNS cells. It was demonstrated that microglial inducible nitric oxide synthase (iNOS) as well as IL-1β levels is increased in the brain of patients suffering from Parkinson’s disease (PD) [4], leading to the hypothesis that the increased levels of iNOS or IL-1β may contribute to the pathophysiology of neurodegenerative disorders, especially for PD [5]. The neurotrophin glial cell line-derived neurotrophic factor (GDNF) has received lots of attention because it has been shown to be a potent survival factor for dopaminergic midbrain [6, 7] and spinal cord neurons [8]. In some pathological circumstances, such as experimental status epilepticus or experimental traumatic

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Discussion

Conclusion