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Effect of Proinflammatory S100A9 Protein on Migration and Proliferation of Microglial Cells

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Abstract

Alzheimer’s disease (AD) is a multifactorial disease affecting aging population worldwide. Neuroinflammation became a focus of research as one of the major pathologic processes relating to the disease onset and progression. Proinflammatory S100A9 is the central culprit in the amyloid-neuroinflammatory cascade implicated in AD and other neurodegenerative diseases. We studied the effect of S100A9 on microglial BV-2 cell proliferation and migration. The responses of BV-2 cells to S100A9 stimulation were monitored in real-time using live cell microscopy, transcriptome sequencing, immunofluorescence staining, western blot analysis, and ELISA. We observed that a low dose of S100A9 promotes migration and proliferation of BV-2 cells. However, acute inflammatory condition (i.e., high S100A9 doses) causes diminished cell viability; it is uncovered that S100A9 activates TLR-4 and TLR-7 signaling pathways, leading to TNF-α and IL-6 expression, which affect BV-2 cell migration and proliferation in a concentration-dependent manner. Interestingly, the effects of S100A9 are not only inhibited by TNF-α and IL-6 antibodies. The addition of amyloid-β (Aβ) 1–40 peptide resumes the capacities of BV-2 cells to the level of low S100A9 concentrations. Based on these results, we conclude that in contrast to the beneficial effects of low S100A9 dose, high S100A9 concentration leads to impaired mobility and proliferation of immune cells, reflecting neurotoxicity at acute inflammatory conditions. However, the formation of Aβ plaques may be a natural mechanism that rescues cells from the proinflammatory and cytotoxic effects of S100A9, especially considering that inflammation is one of the primary causes of AD.

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The data that supports the findings of this study are available in the supplementary material of this article.

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Funding

This work was supported by the National Natural Science Foundation of China (51927804), the China Scholarship Council (202106970013), the Natural Science Foundation of Shaanxi Province (2021JM-301), the Youth Innovation Team of Future Medical Support Plan of Chongqing Medical University (No. W0037), and the Swedish Medical Research Council and Infrastructure grant of Medical Faculty, Umeå University (Ludmilla A Morozova-Roche).

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  1. Qiao Bai  and Dan Sun contribute  equally to this work.

Authors and Affiliations

  1. Chongqing Medical University, 1 Medical College Road, Yu Zhong District, Chongqing, China

    Qiao Bai, Xiaoyin Zhang, Li Chen, Xin Zhou, Liu Ye, Yong Tang & Yonggang Liu

  2. State Key Laboratory of Photon-Technology in Western China Energy, Institute of Photonics and Photon-Technology, Northwest University, Xi’an, Shaanxi, China

    Dan Sun, Yang Zeng, Jie Zhu & Ce Zhang

  3. Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden

    Ludmilla A. Morozova-Roche

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  1. Qiao Bai
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  2. Dan Sun
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  3. Yang Zeng
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  4. Jie Zhu
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  5. Ce Zhang
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  10. Yong Tang
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Contributions

Qiao Bai Searching and data collection, Investigation, Data curation, Analyzing, Writing - original draft, prepared all figures. Dan Sun, Yang Zeng, Jie Zhu, Li Chen, Xin Zhou, Liu Ye and Yong Tang searching and data collection, Analyzing, Writing - original draft. Ce Zhang and Yonggang Liu Review & editing. Yonggang Liu Project administration, Supervision, Review & editing. Yonggang Liu Conceptualization, Project administration, Supervision, Review & editing.

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Correspondence to Yonggang Liu.

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Bai, Q., Sun, D., Zeng, Y. et al. Effect of Proinflammatory S100A9 Protein on Migration and Proliferation of Microglial Cells. J Mol Neurosci 73, 983–995 (2023). https://doi.org/10.1007/s12031-023-02168-1

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