S100A9, a member of the S100 family, is a Ca2+ binding protein. It is mainly expressed in neutrophils and monocytes and plays crucial roles in modulating inflammatory responses and inflammation-associated diseases. S100A9 often forms a heterodimer with S100A8, and they are involved in multiple signaling pathways, such as the toll-like receptor 4/MyD88/NF-κB, IL-17-NFκB-caspase-3, and TLR4-NFkB-signaling pathways [1,4,5,6].

In myocardial infarction, short-term blockade of S100A9 inhibits inflammation and improves cardiac function, while long-term blockade has negative impacts on cardiac recovery, showing its dual role in inflammatory and reparatory immune responses [2]. In hepatocellular carcinoma, TACE-induced hypoxia upregulates S100A9 via HIF1A-mediated pathway, promoting tumor growth and metastasis through mitochondrial fission and ROS production [3]. In rosacea, S100A9 exacerbates inflammation by activating toll-like receptor 4/MyD88/NF-κB signaling pathways [4]. In obesity, overexpression of S100A9 impairs macrophage differentiation via TLR4-NFkB-signaling, worsening inflammation and wound healing [6]. In sepsis-induced acute lung injury, S100A9 exacerbates lung damage and epithelial cell apoptosis via the IL-17-NFκB-caspase-3 signaling pathway [5]. In acute pancreatitis, deletion of S100A9 in pancreatic ducts alleviates the disease by inhibiting NLRP3 activation through targeting VNN1-mediated ROS release [7].

In conclusion, S100A9 is a key player in inflammation and various disease conditions. Gene knockout mouse models have been instrumental in revealing its functions in different biological processes and disease areas, including myocardial infarction, cancer, skin diseases, obesity-related disorders, and sepsis-associated organ injuries. These studies provide potential therapeutic targets for treating these diseases by targeting S100A9 or its associated signaling pathways.

References:

1. Chen, Yu, Ouyang, Yuzhen, Li, Zhixin, Wang, Xiufang, Ma, Jian. 2023. S100A8 and S100A9 in Cancer. In Biochimica et biophysica acta. Reviews on cancer, 1878, 188891. doi:10.1016/j.bbcan.2023.188891. https://pubmed.ncbi.nlm.nih.gov/37001615/

2. Marinković, Goran, Koenis, Duco Steven, de Camp, Lisa, Jovinge, Stefan, Schiopu, Alexandru. 2020. S100A9 Links Inflammation and Repair in Myocardial Infarction. In Circulation research, 127, 664-676. doi:10.1161/CIRCRESAHA.120.315865. https://pubmed.ncbi.nlm.nih.gov/32434457/

3. Zhong, Chengrui, Niu, Yi, Liu, Wenwu, Yuan, Yunfei, Li, Binkui. 2022. S100A9 Derived from Chemoembolization-Induced Hypoxia Governs Mitochondrial Function in Hepatocellular Carcinoma Progression. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 9, e2202206. doi:10.1002/advs.202202206. https://pubmed.ncbi.nlm.nih.gov/36041055/

4. Le, Yan, Zhang, Jiawen, Lin, Yi, Xiang, Leihong, Zhang, Chengfeng. 2024. S100A9 Exacerbates the Inflammation in Rosacea through Toll-Like Receptor 4/MyD88/NF-κB Signaling Pathway. In The Journal of investigative dermatology, 144, 1985-1993.e1. doi:10.1016/j.jid.2024.02.012. https://pubmed.ncbi.nlm.nih.gov/38447867/

5. Pei, Hui, Chen, Jianming, Qu, Jie, Lu, Zhongqiu. 2024. S100A9 exacerbates sepsis-induced acute lung injury via the IL17-NFκB-caspase-3 signaling pathway. In Biochemical and biophysical research communications, 710, 149832. doi:10.1016/j.bbrc.2024.149832. https://pubmed.ncbi.nlm.nih.gov/38588614/

6. Franz, Sandra, Ertel, Anastasia, Engel, Kathrin M, Simon, Jan C, Saalbach, Anja. 2022. Overexpression of S100A9 in obesity impairs macrophage differentiation via TLR4-NFkB-signaling worsening inflammation and wound healing. In Theranostics, 12, 1659-1682. doi:10.7150/thno.67174. https://pubmed.ncbi.nlm.nih.gov/35198063/

7. Xiang, Hong, Guo, Fangyue, Tao, Xufeng, Li, Lunxu, Shang, Dong. 2021. Pancreatic ductal deletion of S100A9 alleviates acute pancreatitis by targeting VNN1-mediated ROS release to inhibit NLRP3 activation. In Theranostics, 11, 4467-4482. doi:10.7150/thno.54245. https://pubmed.ncbi.nlm.nih.gov/33754072/