S100A9 blockade prevents lipopolysaccharide-induced lung injury via suppressing the NLRP3 pathway

  • Respir Res. 2021 Feb 6;22(1):45. doi: 10.1186/s12931-021-01641-y.
Boying Zhao   #  1  2 ,  Renfu Lu   #  1 ,  Jianjun Chen  1 ,  Ming Xie  1 ,  Xingji Zhao  3 ,  Lingwen Kong  4
Affiliations
  • 1. Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, No. 1 Jiangkang Road, Yuzhong, Chongqing, 400010, China.
  • 2. Vascular Surgery Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3. Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, No. 1 Jiangkang Road, Yuzhong, Chongqing, 400010, China. [email protected].
  • 4. Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, No. 1 Jiangkang Road, Yuzhong, Chongqing, 400010, China. [email protected].
  • # Contributed equally.
PMID: 33549095 DOI: 10.1186/s12931-021-01641-y
Abstract

Background: S100 calcium binding protein A9 (S100A9) is a pro-inflammatory alarmin associated with several inflammation-related diseases. However, the role of S100A9 in lung injury in sepsis has not been fully investigated. Therefore, the present study aimed to determine the role of S100A9 in a lipopolysaccharide (LPS)-induced lung injury murine model and its underlying molecular mechanisms.

Methods: LPS was utilized to induce sepsis and lung injury in C57BL/6 or NOD-like Receptor family pyrin domain containing 3 (NLRP3)-/- mice. To investigate the effects of S100A9 blockade, mice were treated with a specific inhibitor of S100A9. Subsequently, lung injury and inflammation were evaluated by histology and enzyme‑linked immunosorbent assay (ELISA), respectively. Furthermore, western blot analysis and RT-qPCR were carried out to investigate the molecular mechanisms underlying the effects of S100A9.

Results: S100A9 was upregulated in the lung tissues of LPS-treated mice. However, inhibition of S100A9 alleviated LPS-induced lung injury. Additionally, S100A9 blockade also attenuated the inflammatory responses and Apoptosis in the lungs of LPS-challenged mice. Furthermore, the increased expression of NLRP3 was also suppressed by S100A9 blockade, while S100A9 blockade had no effect on NLRP3-/- mice. In vitro, S100A9 downregulation mitigated LPS-induced inflammation. Interestingly, these effects were blunted by NLRP3 overexpression.

Conclusion: The results of the current study suggested that inhibition of S100A9 could protect against LPS-induced lung injury via inhibiting the NLRP3 pathway. Therefore, S100A9 blockade could be considered as a novel therapeutic strategy for lung injury in sepsis.

Keywords
Acute lung injury; Inflammatory alarmin; NLRP3; S100A9.
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