S100a9, a member of the S100 family, is a Ca2+ binding protein. It is mainly expressed in neutrophils and monocytes, playing crucial roles in modulating inflammatory responses. It often forms a heterodimer with S100A8 (S100A8/A9) and is involved in multiple signaling pathways such as Toll-like receptor 4/MyD88/NF-κB, IL-17-NFκB-caspase-3, and others, which are related to various inflammation-associated diseases [1,4,6].

In myocardial infarction, short-term S100A9 blockade during the inflammatory phase is beneficial, while long-term blockade leads to progressive cardiac function deterioration, indicating its role in both inflammatory and reparatory immune responses [2]. In hepatocellular carcinoma, S100A9, induced by chemoembolization-induced hypoxia via the HIF1A-mediated pathway, promotes tumor growth and metastasis through regulating mitochondrial fission and reactive oxygen species production [3]. In rosacea, S100A9 exacerbates inflammation by activating the Toll-like receptor 4/MyD88/NF-κB signaling pathway [4]. In psoriasis and psoriatic arthritis, keratinocyte-derived S100A9 modulates neutrophil infiltration, and S100A9/CP may be a marker for identifying patients with psoriasis at risk of developing psoriatic arthritis [5]. In sepsis-induced acute lung injury, S100A9 exacerbates lung damage and epithelial cell apoptosis via the IL-17-NFκB-caspase-3 signaling pathway [6]. In obesity, S100A9 overexpression impairs macrophage differentiation, worsening inflammation and wound healing [7]. In sepsis-induced acute liver injury, S100A9 deficiency alleviates liver injury by regulating AKT-AMPK-dependent mitochondrial energy metabolism [8]. In acute pancreatitis, pancreatic ductal deletion of S100A9 alleviates the condition by targeting VNN1-mediated ROS release to inhibit NLRP3 activation [9].

In conclusion, S100a9 is a key player in inflammation-related processes and various diseases, including myocardial infarction, cancer, skin diseases, and sepsis-associated organ injuries. Gene knockout (KO) and conditional knockout (CKO) mouse models have been instrumental in revealing its functions in these disease conditions, providing insights into potential therapeutic strategies targeting S100a9.

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. Mellor, Liliana F, Gago-Lopez, Nuria, Bakiri, Latifa, Schett, Georg, Wagner, Erwin F. 2022. Keratinocyte-derived S100A9 modulates neutrophil infiltration and affects psoriasis-like skin and joint disease. In Annals of the rheumatic diseases, 81, 1400-1408. doi:10.1136/annrheumdis-2022-222229. https://pubmed.ncbi.nlm.nih.gov/35788494/

6. 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/

7. 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/

8. Zhang, Yanting, Wu, Feng, Teng, Fei, Guo, Shubin, Li, Huihua. 2023. Deficiency of S100A9 Alleviates Sepsis-Induced Acute Liver Injury through Regulating AKT-AMPK-Dependent Mitochondrial Energy Metabolism. In International journal of molecular sciences, 24, . doi:10.3390/ijms24032112. https://pubmed.ncbi.nlm.nih.gov/36768433/

9. 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/