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GDNF fails to inhibit LPS-mediated activation of mouse microglia
1Institute for Anatomy and Cell Biology, Department of Molecular Embryology, Albert-Ludwigs-University Freiburg, Germany.
Abstract:
GDNF is a potent neuroprotective factor for midbrain dopaminergic (mDA) neurons. In LPS-mediated models for mDA degeneration GDNF increases neuron survival and further reduces microglia activation. To elucidate the effects of GDNF on LPS-induced activation, primary microglia from C57BL/6 and NMRI mice have been analysed. In this study we demonstrate that GDNF is not able to inhibit LPS-mediated upregulation and release of the proinflammatory factors IL6 and TNFα. Moreover, we provide evidence that mouse microglia, in contrast to rat microglia, lack expression of the GDNF signalling receptor c-Ret resulting in abrogated activation of downstream signalling kinases Akt and Erk1/2.
Insights
Glial cell-derived neurotrophic factor (GDNF) does not inhibit inflammation in mouse microglia. Mouse microglia lack the GDNF receptor (c-Ret), preventing downstream signaling and neuroprotection against inflammatory triggers.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Glial cell-derived neurotrophic factor (GDNF) is recognized for its neuroprotective properties, particularly for midbrain dopaminergic (mDA) neurons.
- GDNF has shown efficacy in reducing mDA neuron degeneration and mitigating microglial activation in specific models.
Purpose of the Study:
- To investigate the precise effects of GDNF on lipopolysaccharide (LPS)-induced activation in primary mouse microglia.
- To determine if GDNF can modulate the release of pro-inflammatory factors in response to LPS stimulation.
Main Methods:
- Primary microglia cultures were established from C57BL/6 and NMRI mouse strains.
- Cells were treated with LPS to induce inflammatory responses.
- Analysis included assessing the expression and release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα).
- Investigated the expression of the GDNF signaling receptor c-Ret and downstream kinases Akt and Erk1/2.
Main Results:
- GDNF failed to inhibit the LPS-induced upregulation and release of pro-inflammatory cytokines IL-6 and TNFα in mouse microglia.
- Mouse microglia were found to lack the expression of the GDNF signaling receptor c-Ret.
- This absence of c-Ret resulted in the abrogation of downstream signaling pathways, including the activation of Akt and Erk1/2 kinases.
Conclusions:
- GDNF does not exert anti-inflammatory effects on LPS-activated mouse microglia.
- The lack of c-Ret receptor expression in mouse microglia is responsible for the inability of GDNF to modulate inflammatory responses and downstream signaling.
- Findings highlight species-specific differences in microglial responses to GDNF, contrasting with observations in rat microglia.
