S100a8, also known as MRP8, is a Ca2+ binding protein belonging to the S100 family. It often exists as a heterodimer with S100a9 (MRP14) and functions as a Ca2+ sensor in neutrophils and monocytes, participating in cytoskeleton rearrangement, arachidonic acid metabolism, and modulating inflammatory responses. It is also involved in multiple signaling pathways in tumor cells [1,2].

In MI/R injury mouse models, knockout of S100a9, a part of the S100a8/a9 complex, markedly decreased cardiomyocyte death and improved heart function, while hematopoietic overexpression of S100a9 exacerbated the injury. This shows that S100a8/a9 signaling causes mitochondrial respiratory dysfunction in cardiomyocytes, and targeting it may be a novel therapeutic intervention [3]. In diabetic nephropathy, knocking down S100A8/A9 in mouse models alleviated renal interstitial fibrosis, while over-expression promoted it. High levels of S100A8/A9 activated the TLR4/NF-κB signal pathway, which promoted the EMT process and RIF progression [4].

In conclusion, S100a8, mainly in the form of S100a8/a9 heterodimer, plays crucial roles in inflammation-related processes and diseases. Gene knockout or knockdown in mouse models have revealed its key role in MI/R injury and diabetic nephropathy, providing potential therapeutic targets for these diseases.

References:

1. Wang, Siwen, Song, Rui, Wang, Ziyi, Wang, Shaoxiong, Ma, Jian. 2018. S100A8/A9 in Inflammation. In Frontiers in immunology, 9, 1298. doi:10.3389/fimmu.2018.01298. https://pubmed.ncbi.nlm.nih.gov/29942307/

2. 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/

3. Li, Yulin, Chen, Boya, Yang, Xinying, Ma, Xin-Liang, Du, Jie. 2019. S100a8/a9 Signaling Causes Mitochondrial Dysfunction and Cardiomyocyte Death in Response to Ischemic/Reperfusion Injury. In Circulation, 140, 751-764. doi:10.1161/CIRCULATIONAHA.118.039262. https://pubmed.ncbi.nlm.nih.gov/31220942/

4. Du, Lei, Chen, Yibing, Shi, Jiasen, Yin, Xiaoxing, Lu, Qian. 2022. Inhibition of S100A8/A9 ameliorates renal interstitial fibrosis in diabetic nephropathy. In Metabolism: clinical and experimental, 144, 155376. doi:10.1016/j.metabol.2022.155376. https://pubmed.ncbi.nlm.nih.gov/36521551/