S100A9 blockade improves the functional recovery after spinal cord injury via mediating neutrophil infiltration

Feng Sun; Haiwei Zhang; Tianwen Huang; Jianhui Shi; Tianli Wei; Yansong Wang

doi:10.3892/etm.2022.11220

S100A9 blockade improves the functional recovery after spinal cord injury via mediating neutrophil infiltration

Exp Ther Med. 2022 Apr;23(4):291. doi: 10.3892/etm.2022.11220. Epub 2022 Feb 17.

Authors

Feng Sun^{1

2}, Haiwei Zhang³, Tianwen Huang², Jianhui Shi⁴, Tianli Wei¹, Yansong Wang¹

Affiliations

¹ Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, P.R. China.
² Department of Orthopedics, General Hospital of Heilongjiang General Administration of Agriculture and Reclamation, Harbin, Heilongjiang 150000, P.R. China.
³ Department of Imaging, General Hospital of Heilongjiang General Administration of Agriculture and Reclamation, Harbin, Heilongjiang 150000, P.R. China.
⁴ Department of Orthopaedics, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150000, P.R. China.

Abstract

Spinal cord injury (SCI) refers to damage to the spinal cord resulting from trauma, disease or degeneration. Controlling the inflammatory process and restoring neural homeostasis is hypothesized to prevent injury aggravation. S100 calcium-binding protein A9 (S100A9) is a pro-inflammatory alarm protein, which is expressed in and released by activated neutrophils. However, whether S100A9 could serve as an effective target for the treatment of SCI has not been reported to date. In the present study, a T10 spinal cord contusion injury model was established in Sprague-Dawley rats. S100A9 expression level was determined in the serum and injured spinal cord tissue via ELISA, reverse transcription-quantitative PCR (RT-qPCR) and western blotting. The S100A9-specific blocker, ABR-238901 (ABR), was administered during the inflammatory phase of SCI, as a form of treatment. Subsequently, the morphological structure, neuronal viability and inflammatory levels of injured spinal cord were observed by histopathology, immunohistochemistry and RT-qPCR. In the obtained results, S100A9 was found to be highly expressed in the injured spinal cord and serum in the first 3 days after SCI. However, at 28 days after surgery, ABR treatment significantly improved motor function, reduced the cavity formation and neutrophil infiltration in the lesion, which was verified via H&E staining and immunohistochemistry for myeloperoxidase. Furthermore, ABR treatment was found to effectively improve the survival and viability of neurons, as shown via Nissl staining and immunofluorescence of the synaptic plasticity markers, microtubule associated protein 2 and neurofilament 200. Moreover, S100A9 blockade effectively upregulated the mRNA expression level of the anti-inflammatory genes, IL-4 and IL-10 and downregulated the mRNA expression level of the pro-inflammatory factors, IL-1β, IL-6 and TNF-α. In addition, S100A9 blockade notably alleviated the apoptosis level of the injured nerve cells. Therefore, the findings of the present study revealed that S100A9 may be a useful target for the treatment of SCI.

Keywords: S100A9; inflammation; neurodegeneration; neutrophils; spinal cord injury.

Grants and funding

Funding: This study has been financially supported by the National Natural Science Foundation of China (grant no. 81871781).