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<p>Following cerebral ischemia, brain-derived neurotrophic factor (BDNF) expressed by Iba-1⁺ microglia may support neuronal survival and plasticity, yet the micro-environmental cues that drive this phenotype remain largely uncharacterized. In the present study, we addressed three unresolved questions: whether peripherally derived Ly6C⁺ macrophages contribute to the BDNF⁺/Iba-1⁺ microglial pool; which cytokine is responsible for inducing BDNF expression; and what cellular source provides this signal. Using a rat distal middle cerebral artery occlusion (dMCAO) model, we performed multi-label confocal immunofluorescence and stereotaxic intracortical injection of an IL-4 neutralizing antibody, with analyses conducted at 48&#xa0;h post-ischemia. We first established that Ly6C⁺, Iba-1⁺, and CD14⁺ cells represent three phenotypically distinct populations in the ischemic hemisphere. Quantitative mapping revealed that BDNF⁺/Iba-1⁺ microglia were mainly distributed in the infarct boundary zone, peri-infarct cortex, corpus callosum, and striatum, a pattern that closely mirrored the spatial distribution of IL-4⁺/neutrophil elastase⁺ neutrophils. IL-4 neutralization significantly reduced both the absolute number of BDNF⁺/Iba-1⁺ cells and their proportion among total Iba-1⁺ cells across these regions. Moreover, IL-4 blockade markedly attenuated the phenotypic conversion of Ly6C⁺ macrophages into Iba-1⁺ cells, indicating that endogenous IL-4 in the ischemic microenvironment facilitates both BDNF induction and the adoption of a microglia-like phenotype by infiltrating macrophages. These findings identify neutrophil-derived IL-4 as a critical neuro-immune mediator that shapes a BDNF-enriched microenvironment in the post-ischemic brain. This neutrophil–microglia axis may represent a novel therapeutic target to sustain beneficial microglial functions and promote recovery after stroke.</p>

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Neutrophil-derived IL-4 induces BDNF expression in microglia within the infarct cortex and surrounding regions following cerebral ischemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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  • Yunqian Guan,
  • Xinwei Zang,
  • Xiaobo Li,
  • Danni Chen,
  • Wanting Xing,
  • Bochao Liu,
  • Haiqiang Zou,
  • Zhiguo Chen

摘要

Following cerebral ischemia, brain-derived neurotrophic factor (BDNF) expressed by Iba-1⁺ microglia may support neuronal survival and plasticity, yet the micro-environmental cues that drive this phenotype remain largely uncharacterized. In the present study, we addressed three unresolved questions: whether peripherally derived Ly6C⁺ macrophages contribute to the BDNF⁺/Iba-1⁺ microglial pool; which cytokine is responsible for inducing BDNF expression; and what cellular source provides this signal. Using a rat distal middle cerebral artery occlusion (dMCAO) model, we performed multi-label confocal immunofluorescence and stereotaxic intracortical injection of an IL-4 neutralizing antibody, with analyses conducted at 48 h post-ischemia. We first established that Ly6C⁺, Iba-1⁺, and CD14⁺ cells represent three phenotypically distinct populations in the ischemic hemisphere. Quantitative mapping revealed that BDNF⁺/Iba-1⁺ microglia were mainly distributed in the infarct boundary zone, peri-infarct cortex, corpus callosum, and striatum, a pattern that closely mirrored the spatial distribution of IL-4⁺/neutrophil elastase⁺ neutrophils. IL-4 neutralization significantly reduced both the absolute number of BDNF⁺/Iba-1⁺ cells and their proportion among total Iba-1⁺ cells across these regions. Moreover, IL-4 blockade markedly attenuated the phenotypic conversion of Ly6C⁺ macrophages into Iba-1⁺ cells, indicating that endogenous IL-4 in the ischemic microenvironment facilitates both BDNF induction and the adoption of a microglia-like phenotype by infiltrating macrophages. These findings identify neutrophil-derived IL-4 as a critical neuro-immune mediator that shapes a BDNF-enriched microenvironment in the post-ischemic brain. This neutrophil–microglia axis may represent a novel therapeutic target to sustain beneficial microglial functions and promote recovery after stroke.