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Published on: September 4, 2013
JAK2/STAT3 pathway regulates microglia polarization involved in hippocampal inflammatory damage due to acute paraquat
Zhuo Fan1, Wendi Zhang1, Qi Cao1
1Department of Occupational Health and Environmental Health, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei 050000, China; Hebei Province Key Laboratory of Environment and Human Health, Shijiazhuang, Hebei 050000, China.
Objective:
To explore the effects of acute paraquat (PQ) exposure on the phenotypic polarization of hippocampal microglia and its mechanism.
Methods:
An acute PQ exposure rat model was established. Male SD rats were exposed to 0, 5, 25, and 50 mg/kg PQ, and brain hippocampal tissue was collected after 1, 3, and 7 days of exposure, respectively. Hippocampal pathological changes were examined by H&E staining, and immunohistochemistry (IHC) was used to detect changes in the number of Iba-1-positive cells, the average number of endpoints, and the average process length. The protein expression of Iba-1 was detected by western blotting. BV-2 microglia were treated with 0, 0.01, 0.025, 0.05, or 0.1 μmol/L PQ for 24 h. ELISA and western blotting assays were performed to detect the expression of TNF-α and IL-1β in vivo and in vitro. The M1 microglia marker iNOS, the M2 microglia marker Arg-1, and the p-JAK2 and p-STAT3 protein were detected by western blotting. JAK2/STAT3 pathway activation role in regulating microglia phenotypic polarization was further validated in vivo and in vitro by JAK2-specific inhibitor AG490 administration.
Results:
After acute PQ exposure, hippocampal neurons showed pathological changes such as loose arrangement and nuclear pyknosis, the number of Iba-1 positive cells and the expression of Iba-1 protein increased, and the average number of endpoints and average process length of microglia decreased. Histological examination revealed that compared with the control group, in the 50 mg/kg PQ group on the 3rd and 7th day, the expression of TNF-α, IL-1β, and iNOS significantly increased, while that of Arg-1 significantly decreased. p-JAK2 and p-STAT3 expression significantly increased in the 50 mg/kg PQ group on the 1st, 3rd, and 7th day. In vitro, compared with the control group, the expression of TNF-α, IL-1β, iNOS, p-JAK2, and p-STAT3 significantly increased, while Arg-1 expression was significantly reduced in the 0.025, 0.05, and 0.1 μmol/L PQ groups. After AG490 administration, the expression levels of p-JAK2, p-STAT3, iNOS, TNF-α, and IL-1β in the AG490 +PQ group were significantly inhibited in vivo and in vitro compared with the PQ-only group. On the contrary, Arg-1 expression was significantly increased.
Conclusion:
Our results suggest that acute PQ exposure may induce M1-type polarization of hippocampal microglia by activating the JAK2/STAT3 pathway, which in turn releases pro-inflammatory factors such as TNF-α and IL-1β, leading to hippocampal inflammatory damage.
Insights
Acute paraquat (PQ) exposure triggers M1-type polarization in hippocampal microglia via the JAK2/STAT3 pathway. This leads to increased pro-inflammatory factors and hippocampal damage.
Area of Science:
- Neuroscience
- Toxicology
- Immunology
Background:
- Microglia play crucial roles in brain immunity and homeostasis.
- Paraquat (PQ) is a herbicide known for its neurotoxic effects.
- Understanding PQ's impact on microglia is vital for neuroprotection strategies.
Purpose of the Study:
- To investigate the effects of acute paraquat (PQ) exposure on hippocampal microglia.
- To elucidate the underlying mechanism, focusing on microglial phenotypic polarization.
- To examine the role of the JAK2/STAT3 pathway in PQ-induced microglial changes.
Main Methods:
- Established an acute PQ exposure rat model with varying doses (0-50 mg/kg).
- Analyzed hippocampal tissue using H&E staining, immunohistochemistry, and western blotting.
- Utilized BV-2 microglia cell cultures treated with PQ and JAK2 inhibitor AG490.
Main Results:
- PQ exposure induced hippocampal neuronal damage and increased microglial activation (Iba-1+ cells).
- PQ promoted M1 microglia polarization (increased iNOS, TNF-α, IL-1β; decreased Arg-1).
- PQ activated the JAK2/STAT3 pathway, which was reversed by AG490, mitigating M1 polarization.
Conclusions:
- Acute paraquat exposure induces M1-type polarization of hippocampal microglia.
- The JAK2/STAT3 pathway is a key mediator in PQ-induced microglial M1 polarization.
- This process contributes to hippocampal inflammatory damage via pro-inflammatory factor release.
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