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IL-4 Switches Microglia/macrophage M1/M2 Polarization and Alleviates Neurological Damage by Modulating the JAK1/STAT6
Yang He1, Yang Gao1, Qiang Zhang1
1Department of Cerebrovascular Disease, Affiliated Hospital of Zunyi Medical University, No.149, Dalian Road, Zunyi 563000, China.
Abstract:
Inflammatory damage following ICH is often attributed to microglia/macrophage activation. In many diseases, IL-4 has been proven to switch microglia/macrophages from the pro-inflammatory to the anti-inflammatory subtype. However, the role and underlying mechanism of IL-4 in ICH, especially in neuroprotection, remain unknown. In our study, we constructed a microglia/macrophage polarization model in BV2 cells to verify that the M2 shift of microglia/macrophages was mediated by JAK1/STAT6 after IL-4 treatment and then revealed that in vitro administration of IL-4 decreased M1 markers, pro-inflammatory cytokines and neuroapoptosis markers but significantly increased M2 markers and anti-inflammatory cytokines. Using an ICH model in mice, we observed that IL-4 administration decreased neurological deficits, brain edema and infarct lesions induced by ICH. We verified that IL-4 mediates inflammation by regulating M1/M2 polarization in ICH and explored the underlying mechanism. Furthermore, we discovered that pathway components and apoptosis-related proteins showed consistent trends based on their respective roles, and inferred that the process that TNF-α activates caspase-3 may be the crosstalk that microglia phagocytosis developed into accelerate apoptosis of cells in ICH. In conclusion, our study demonstrates that IL-4 may promote M2 microglia/macrophage polarization partly through the JAK1/STAT6 pathway to alleviate neuroinflammation after ICH.
Insights
Interleukin-4 (IL-4) reduces brain damage after intracerebral hemorrhage (ICH) by shifting microglia/macrophages to an anti-inflammatory state via the JAK1/STAT6 pathway, promoting neuroprotection.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Intracerebral hemorrhage (ICH) causes significant inflammatory damage, primarily mediated by microglia/macrophage activation.
- Interleukin-4 (IL-4) is known to modulate microglia/macrophages from pro-inflammatory to anti-inflammatory phenotypes in various conditions.
Purpose of the Study:
- To investigate the role and mechanism of IL-4 in neuroprotection following ICH.
- To determine if IL-4 influences microglia/macrophage polarization in the context of ICH.
Main Methods:
- Established a microglia/macrophage polarization model in BV2 cells and an ICH mouse model.
- Administered IL-4 to assess its effects on M1/M2 polarization markers, pro-inflammatory and anti-inflammatory cytokines, and neuroapoptosis markers.
- Analyzed the involvement of the JAK1/STAT6 pathway and apoptosis-related proteins.
Main Results:
- IL-4 treatment induced M2 microglia/macrophage polarization via the JAK1/STAT6 pathway in vitro.
- In vivo, IL-4 administration significantly reduced neurological deficits, brain edema, and infarct lesions in ICH mice.
- IL-4 modulated M1/M2 polarization, decreased pro-inflammatory cytokines, and reduced neuroapoptosis markers post-ICH.
Conclusions:
- IL-4 promotes M2 microglia/macrophage polarization through the JAK1/STAT6 pathway, thereby alleviating neuroinflammation and neuroprotection after ICH.
- The study identified potential crosstalk between TNF-α activation of caspase-3 and microglia phagocytosis in accelerating apoptosis during ICH.
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