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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
J147 modulates microglial polarization via CAMKK2/AMPK signaling to ameliorate neuroinflammation
Liufang He1, Tahir Ali2, Tingyan Wei1
1Department of Neonatology, People's Hospital of Longhua, Shenzhen 518109, China.
Abstract:
Neuroinflammation, characterized by an imbalance in microglial polarization, significantly contributes to various neurological conditions, including brain injuries, and represents a key therapeutic target for these conditions. This study aimed to determine whether J147, a known neuroprotective compound, could avert neuroinflammation by influencing microglial responses via CAMKK2/AMPK signaling. Employing an LPS-induced neuroinflammation model, we demonstrate that J147 exhibits strong anti-inflammatory effects in vivo, protecting brain structure and rebalancing cytokine profiles (e.g., suppressing TNF-α/IL-6 while enhancing IL-10). Cellularly, J147 induced a functional switch from M1 (iNOS+, CD40+) to M2 (CD206+, IL-10+) microglial phenotypes, consistent across both in vivo brain samples and in vitro microglial cultures, indicating a strong anti-inflammatory reprogramming effect. Additionally, J147 improved LPS-suppressed CAMKK2/AMPK phosphorylation. However, pharmacological inhibitors (STO-609/dorsomorphin) of the CAMKK2/AMPK signaling cascades abolished J147's neuroprotective effects, indicating that J147's neuroprotective potential is CAMKK2/AMPK-dependent. Complementary in vitro studies using microglia-oligodendrocyte co-cultures validated J147's dual functionality, restoring microglial viability (90 % recovery versus LPS) while promoting M2 polarization and maintaining oligodendrocyte integrity (85 % increase in MBP), all of which is contingent upon intact CAMKK2/AMPK signaling.
Insights
The compound J147 reduces neuroinflammation by shifting microglial cells to an anti-inflammatory state, protecting brain structure and function through CAMKK2/AMPK signaling.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuroinflammation, driven by microglial polarization imbalance, is central to neurological disorders like brain injuries.
- Targeting microglial responses offers a promising therapeutic avenue for neuroinflammatory conditions.
Purpose of the Study:
- To investigate if the neuroprotective compound J147 can mitigate neuroinflammation.
- To explore J147's mechanism of action on microglial polarization via CAMKK2/AMPK signaling.
Main Methods:
- Utilized an LPS-induced neuroinflammation model in vivo and in vitro.
- Assessed microglial polarization (M1/M2 phenotypes) and cytokine profiles.
- Examined the role of CAMKK2/AMPK signaling using pharmacological inhibitors (STO-609, dorsomorphin).
- Evaluated J147's effects on oligodendrocyte integrity in co-cultures.
Main Results:
- J147 demonstrated significant anti-inflammatory effects in vivo, preserving brain structure and rebalancing cytokines (reduced TNF-α/IL-6, increased IL-10).
- J147 induced a phenotypic switch of microglia from M1 to M2, both in vivo and in vitro.
- J147 enhanced CAMKK2/AMPK phosphorylation, and its neuroprotective effects were dependent on this pathway.
- In co-cultures, J147 restored microglial viability and promoted M2 polarization, preserving oligodendrocyte integrity.
Conclusions:
- J147 effectively averts neuroinflammation by reprogramming microglial polarization towards an M2 phenotype.
- The neuroprotective and anti-inflammatory actions of J147 are mediated through the CAMKK2/AMPK signaling pathway.
- J147 holds potential as a therapeutic agent for neurological conditions involving neuroinflammation and microglial dysfunction.
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