Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 32, Pages 11281-11291Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1685-15.2015
Keywords
focal ischemia; IL-4; microglia; neuron; neurovascular unit; PPARg
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Funding
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [1R01NS084292]
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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 gamma (PPAR gamma) 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) PPAR gamma-dependent phagocytosis of apoptotic neurons. Parenteral administration of IL-4 resulted in augmented brain expression of M2- and PPAR gamma-related genes. Furthermore, IL-4 and PPAR gamma 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.
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