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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglia toxicology in α-synuclein pathology
Han Zhang1, Jieli Zhang2, Xiuna Jing3
1Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China; Department of Neurology, Nanfang Hospital of Southern Medical University, Guangzhou, China.
Abstract:
Oligomeric α-synuclein (α-syn) could activate microglia and induce inflammation to drive the pathogenesis of Parkinson's disease (PD). Our previous study revealed that significant difference of IL6ST in cerebrospinal fluid of PD patients and a decline in IL6ST/JAK2/STAT3 were also observed in α-syn-induced HMC3 cells. JAK2/STAT3 pathway is not only a novel inflammatory pathway but also involved in ferroptosis progress. In this study, our results demonstrated that α-syn could impair cell activity and promote HMC3 cells differentiation into M2 phenotype. Besides, α-syn stimulation led to the inhibit of IL6ST/JAK2/STAT3 pathway and its downstream target, HIF-1α, in HMC3 cells. We further carried out transcriptomic analysis for α-syn-induced HMC3 cells and GSEA showed an association with ferroptosis. Results above implied the role of STAT3 in α-syn induced ferroptosis. Later, we found out α-syn decreased the phosphorylation of STAT3, which contributed to a remarkable morphological change in mitochondria and transcriptional activation of ferroptosis regulation genes (FRGs), such as ASCL4 and SLC7A11. Moreover, α-syn also promoted ferroptosis in microglia by inhibiting P-STAT3 expression and increasing iron metabolism and lipid peroxidation levels, all of which were reversed by the STAT3 activator. In conclusion, the phosphorylation and activation of STAT3 was an important factor that regulated microglia ferroptosis. α-syn stimulation influenced the cell activity, polarization and cellular toxicology in microglia via modulating IL6ST/ JAK2/STAT3/HIF-1α axis.
Insights
Oligomeric alpha-synuclein triggers Parkinson's disease pathology by activating microglia and promoting ferroptosis. STAT3 activation is key to regulating this process, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Oligomeric alpha-synuclein (α-syn) is implicated in Parkinson's disease (PD) pathogenesis through microglial activation and inflammation.
- Previous research indicated altered IL6ST levels in PD patients and a decline in the IL6ST/JAK2/STAT3 pathway in α-syn-stimulated microglia.
- The JAK2/STAT3 pathway is recognized for its role in inflammation and ferroptosis.
Purpose of the Study:
- To investigate the role of the IL6ST/JAK2/STAT3 pathway in α-syn-induced microglial dysfunction and ferroptosis.
- To elucidate the mechanisms by which α-syn affects microglial activity, polarization, and ferroptosis.
Main Methods:
- Utilized α-syn-induced HMC3 cells (a human immortalized microglia cell line).
- Performed transcriptomic analysis and Gene Set Enrichment Analysis (GSEA).
- Assessed cell activity, M2 phenotype differentiation, mitochondrial morphology, and levels of iron metabolism and lipid peroxidation. Investigated the effect of a STAT3 activator.
Main Results:
- α-syn impaired HMC3 cell activity and promoted M2 polarization.
- α-syn inhibited the IL6ST/JAK2/STAT3 pathway and its downstream target HIF-1α.
- Transcriptomic analysis revealed an association between α-syn stimulation and ferroptosis pathways.
- α-syn decreased STAT3 phosphorylation, leading to mitochondrial changes and upregulation of ferroptosis genes (ASCL4, SLC7A11).
- α-syn promoted microglial ferroptosis by inhibiting P-STAT3 and increasing iron metabolism and lipid peroxidation, effects reversed by a STAT3 activator.
Conclusions:
- STAT3 phosphorylation and activation are critical regulators of microglia ferroptosis in the context of α-syn stimulation.
- α-syn influences microglial cell activity, polarization, and ferroptosis via the IL6ST/JAK2/STAT3/HIF-1α axis.
