Merck
  • Home
  • Search Results
  • Neuronal Interleukin-4 as a Modulator of Microglial Pathways and Ischemic Brain Damage.

Neuronal Interleukin-4 as a Modulator of Microglial Pathways and Ischemic Brain Damage.

The Journal of neuroscience : the official journal of the Society for Neuroscience (2015-08-14)
Xiurong Zhao, Huan Wang, Guanghua Sun, Jie Zhang, Nancy J Edwards, Jaroslaw Aronowski
ABSTRACT

After ischemic stroke, various damage-associated molecules are released from the ischemic core and diffuse to the ischemic penumbra, activating microglia and promoting proinflammatory responses that may cause damage to the local tissue. Here we demonstrate using in vivo and in vitro models that, during sublethal ischemia, local neurons rapidly produce interleukin-4 (IL-4), a cytokine with potent anti-inflammatory properties. One such anti-inflammatory property includes its ability to polarize macrophages away from a proinflammatory M1 phenotype to a "healing" M2 phenotype. Using an IL-4 reporter mouse, we demonstrated that IL-4 expression was induced preferentially in neurons in the ischemic penumbra but not in the ischemic core or in brain regions that were spared from ischemia. When added to cultured microglia, IL-4 was able to induce expression of genes typifying the M2 phenotype and peroxisome proliferator activated receptor γ (PPARγ) activation. IL-4 also enhanced expression of the IL-4 receptor on microglia, facilitating a "feedforward" increase in (1) their expression of trophic factors and (2) PPARγ-dependent phagocytosis of apoptotic neurons. Parenteral administration of IL-4 resulted in augmented brain expression of M2- and PPARγ-related genes. Furthermore, IL-4 and PPARγ agonist administration improved functional recovery in a clinically relevant mouse stroke model, even if administered 24 h after the onset of ischemia. We propose that IL-4 is secreted by ischemic neurons as an endogenous defense mechanism, playing a vital role in the regulation of brain cleanup and repair after stroke. Modulation of IL-4 and its associated pathways could represent a potential target for ischemic stroke treatment. Depending on the activation signal, microglia/macrophages (MΦ) can behave as "healing" (M2) or "harmful" (M1). In response to ischemia, damaged/necrotic brain cells discharge factors that polarize MΦ to a M1-like phenotype. This polarization emerges early after stroke and persists for days to weeks, driving secondary brain injury via proinflammatory mediators and oxidative damage. Our study demonstrates that, to offset this M1-like polarization process, sublethally ischemic neurons may instead secrete a potent M2 polarizing cytokine, interleukin-4 (IL-4). In the presence of IL-4 (including when IL-4 is administered exogenously), MΦ become more effective in the cleanup of ischemic debris and produce trophic factors that may promote brain repair. We propose that IL-4 could represent a potential target for ischemic stroke treatment/recovery.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-MAP2 antibody produced in mouse, clone HM-2, ascites fluid
Sigma-Aldrich
5α-Androstan-17β-ol-3-one, purum, ≥99.0% (TLC)
Supelco
Methanol solution, NMR reference standard, 4% in methanol-d4 (99.8 atom % D), NMR tube size 5 mm × 8 in.
Sigma-Aldrich
Methanol solution, NMR reference standard, 4% in methanol-d4 (99.8 atom % D), NMR tube size 3 mm × 8 in.
Sigma-Aldrich
Methanol-12C, 99.95 atom % 12C
Sigma-Aldrich
Anti-NeuN Antibody, clone A60, clone A60, Chemicon®, from mouse
Sigma-Aldrich
Anti-GAPDH Antibody, from chicken, purified by affinity chromatography
Sigma-Aldrich
Acetic acid, ≥99.5%, FCC, FG
Sigma-Aldrich
Citrate Concentrated Solution, BioUltra, for molecular biology, 1 M in H2O
Sigma-Aldrich
Monoclonal Anti-Glial Fibrillary Acidic Protein (GFAP) antibody produced in mouse, clone G-A-5, ascites fluid
Sigma-Aldrich
Citric acid trisodium salt, anhydrous, ≥98% (GC)
Sigma-Aldrich
Acetic acid, for luminescence, BioUltra, ≥99.5% (GC)
Sigma-Aldrich
Citrate Concentrated Solution, BioReagent, suitable for coagulation assays, 4 % (w/v)
Sigma-Aldrich
Methanol, NMR reference standard
Sigma-Aldrich
Acetic acid, natural, ≥99.5%, FG
Sigma-Aldrich
Acetic acid-12C2, 99.9 atom % 12C
Sigma-Aldrich
Methanol, anhydrous, 99.8%
SAFC
Acetic acid, glacial