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S100A9 Induces Macrophage M2 Polarization and Immunomodulatory Role in the Lesion Site After Spinal Cord Injury in Rats

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Abstract

Immune response is pivotal in the secondary injury of spinal cord injury (SCI). Polarization of macrophages (MΦ) influences the immune response in the secondary injury, which is regulated by several immune-related proteins. M2Φ plays the immunomodulatory role in the central nervous system. This study used bioinformatic analysis and machine algorithms to screen hub immune-related proteins after SCI and experimentally investigate the role of the target protein in the M2Φ polarization and immunomodulation in rats and in vitro after SCI. We downloaded GSE151371 and GSE45006, hub immune-related genes were screened using machine learning algorithms, and the expression of S100A9 was verified by datasets. Allen's weight-drop injury SCI model in Sprague–Dawley rat and bone marrow-derived rat MΦ with myelin debris model were used to study the effects of S100A9 on M2Φ polarization and immunomodulation at the lesion site and in vitro. Bioinformatic analysis showed that S100A9 acts as a hub immune-related gene in the SCI patients and rats. S100A9 increased at the lesion site in SCI rats, and its inhibition reduced CD206 and ARG-1 expression. Exogenous S100A9 promoted CD206 and ARG-1 expression in MΦ. S100A9 also increased the expression of PD-L1 and decreased MHC II at the lesion site in SCI rats and MΦ with myelin debris, and enhanced mitochondrial activity in rat MΦ with myelin debris. In conclusion, S100A9 is an indispensable factor in the immune process in secondary injury following SCI.

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Data Availability

The datasets and materials supporting the conclusions of this article are included within the article.

Abbreviations

SCI:

Spinal cord injury

MΦ:

Macrophages

M1Φ:

Macrophages

M2Φ:

Macrophages

PD-L1:

Programmed cell death-ligand 1

MHC:

Major histocompatibility

LASSO:

Least absolute shrinkage and selection operator

RF:

Random Forests

GEO:

Gene Expression Omnibus

CNS:

Central nervous system

PPI:

Protein-protein interaction

ROC:

Receiver operating characteristic curve

ROS:

Reactive oxygen species

DEGs:

Differentially expressed genes

KEGG:

Kyoto Encyclopedia of Genes and Genomes

AUC:

Area under the curve

CD206:

Cell surface mannose receptor

RAGE:

Receptor of advanced glycation end products

TLR4:

Toll-like receptor 4

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Funding

This study was supported by a grant from the National Natural Science Foundation of China (No.: 81870976), "136" Hospital Open Fund of Shanxi Bethune Hospital by the Shanxi Provincial Health Commission (No.: 2021YZ04) and Key Projects to Tackle Key Problems (No.: 2020XM27).

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Authors and Affiliations

  1. Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China

    Junqiao Lv, Zhiqiang Wang, Beiyang Wang, Chen Deng & Lin Sun

  2. Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China

    Wei Wang

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Contributions

LS conceived and designed the work that led to the submission, played an essential role in interpreting the results, and was a significant contributor to the writing of the manuscript. JQL contributed significantly to the data acquisition, analysis, and manuscript preparation. ZQW performed the experiments and contributed to the data acquisition. BYW performed the experiments and contributed to the data acquisition. CD performed the experiments, helped perform the analysis, and engaged in constructive discussions. WW carried out the literature search, data analysis and manuscript editing. All authors read and approved the final manuscript.

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Correspondence to Lin Sun.

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Junqiao Lv and Zhiqiang Wang contributed equally to this work and should be considered co-first authors.

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Lv, J., Wang, Z., Wang, B. et al. S100A9 Induces Macrophage M2 Polarization and Immunomodulatory Role in the Lesion Site After Spinal Cord Injury in Rats. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03920-3

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