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Published on: April 13, 2017
RhoA balances microglial reactivity and survival during neuroinflammation
Renato Socodato1, Artur Rodrigues-Santos2, Joana Tedim-Moreira2,3
1Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal. renato.socodato@ibmc.up.pt.
Abstract:
Microglia are the largest myeloid cell population in the brain. During injury, disease, or inflammation, microglia adopt different functional states primarily involved in restoring brain homeostasis. However, sustained or exacerbated microglia inflammatory reactivity can lead to brain damage. Dynamic cytoskeleton reorganization correlates with alterations of microglial reactivity driven by external cues, and proteins controlling cytoskeletal reorganization, such as the Rho GTPase RhoA, are well positioned to refine or adjust the functional state of the microglia during injury, disease, or inflammation. Here, we use multi-biosensor-based live-cell imaging approaches and tissue-specific conditional gene ablation in mice to understand the role of RhoA in microglial response to inflammation. We found that a decrease in RhoA activity is an absolute requirement for microglial metabolic reprogramming and reactivity to inflammation. However, without RhoA, inflammation disrupts Ca2+ and pH homeostasis, dampening mitochondrial function, worsening microglial necrosis, and triggering microglial apoptosis. Our results suggest that a minimum level of RhoA activity is obligatory to concatenate microglia inflammatory reactivity and survival during neuroinflammation.
Insights
A minimum level of RhoA activity is essential for microglia survival and inflammatory responses during neuroinflammation. Without RhoA, inflammation leads to cell death, highlighting RhoA
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Microglia, the brain's primary immune cells, modulate homeostasis but can cause damage when over-activated.
- Cytoskeletal dynamics, regulated by proteins like RhoA, influence microglial functional states during neuroinflammation.
- Understanding RhoA's role is crucial for targeting microglial responses in brain injury and disease.
Purpose of the Study:
- To investigate the function of RhoA in microglial inflammatory responses.
- To elucidate the impact of RhoA deficiency on microglial survival and homeostasis during inflammation.
Main Methods:
- Utilized multi-biosensor live-cell imaging.
- Employed tissue-specific conditional gene ablation in mouse models.
- Assessed microglial metabolic reprogramming, reactivity, and cell death pathways.
Main Results:
- Reduced RhoA activity is necessary for microglial metabolic reprogramming and inflammatory reactivity.
- Loss of RhoA disrupts calcium and pH homeostasis, impairs mitochondrial function, and increases microglial necrosis and apoptosis.
- A basal level of RhoA activity is required for microglial survival during inflammatory conditions.
Conclusions:
- RhoA is a critical regulator of microglial inflammatory responses and survival.
- Targeting RhoA may offer therapeutic strategies for neuroinflammatory diseases by balancing microglial reactivity and viability.
