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Targeting the interactions between neutrophils and microglia: a novel strategy for anti-inflammatory treatment of stroke

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Stroke is the second leading cause of mortality and the leading cause of adult disability worldwide. Neuroinflammation is a crucial mechanism that regulates the pathogenesis and prognosis of stroke and involves both peripheral and intracerebral immune cells. Neutrophils and microglia are the primary immune cells that mediate neuroinflammation and play bidirectional roles after stroke. Significant interactions between neutrophils and microglia exist. Microglia regulate the activation, infiltration, as well as formation of neutrophil extracellular traps (NETs), whereas neutrophils regulate the polarization and phagocytic activity of microglia. In this review, we summarize the bidirectional roles of neutrophils and microglia in stroke with an emphasis on the interactions between neutrophils and microglia, as well as the associated signaling pathways and targets involved. We further introduce potential stroke treatment drugs that regulate the interactions between neutrophils and microglia, including anti-inflammatory drugs and natural products. We propose that, according to the different ischemic times and cell activation states, regulating the interactions between neutrophils and microglia through relevant targets and signaling pathways may be an ideal strategy for the anti-inflammatory treatment of stroke, potentially improving treatment and prognosis of stroke.

This review summarizes the bidirectional roles of neutrophils and microglia in stroke, respectively, focusing on the interactions and signaling pathways between neutrophils and microglia, as well as potential therapeutic targets and drugs.

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Fig. 1: The biphasic roles of neutrophils in stroke.
Fig. 2: The biphasic roles of microglia in stroke.
Fig. 3: The interactions between neutrophils and microglia in stroke.
Fig. 4: The signaling pathways regulating the interactions between neutrophils and microglia.

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Acknowledgements

This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-1-015); National Natural Science Foundation of China (82474112, 82360788); Open Project of State Key Laboratory of Neurology and Oncology Drug Development (SKLSIM-F-202456).

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  1. Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Long-rui Wang, Zi-yuan Zhao, Yin-ru Jiang, Wen-jing Sun, Guan-hua Du & Ling-lei Kong

  2. Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, 030006, China

    Zhao-wei Li

  3. Department of Physiology, Baotou Medical College, Baotou, 014040, China

    Rui-li Shi

  4. State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210042, China

    Ling-lei Kong

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Wang, Lr., Zhao, Zy., Li, Zw. et al. Targeting the interactions between neutrophils and microglia: a novel strategy for anti-inflammatory treatment of stroke. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01662-z

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