Slc22a17, also known as the neutrophil gelatinase-associated lipocalin/lipocalin-2 (LCN2)/24p3 receptor, is an atypical member of the SLC22 family. It is involved in receptor-mediated endocytosis (RME) of LCN2, playing roles in iron-handling, extracellular matrix remodeling, and tight-junction regulation. It is associated with multiple biological pathways including those related to cell death, metabolism, and cancer-related processes [2,3,5]. Genetic models, such as gene knockout mouse models, are valuable for studying its functions.

In a mouse model of transient focal cerebral ischemia, endothelial expression of Slc22a17 increased along with blood-brain barrier (BBB) leakage. Knockdown of Slc22a17 using short interfering RNA in human brain endothelial cultures prevented TNF-α-induced ferroptosis, down-regulation of tight-junction proteins, and disruption of transcellular permeability. In the same model, Slc22a17 knockdown also ameliorated BBB leakage, suggesting its role in controlling BBB function after cerebral ischemia [1]. In another study, in macrophages, knockdown of Slc22a17 reduced MMP9 release upon treatment with recombinant LCN2, indicating its role in the LCN2-mediated regulation of MMP9 in the context of cardiac injury post-myocardial infarction [4].

In conclusion, Slc22a17 is crucial in processes like BBB integrity maintenance after cerebral ischemia and in the LCN2-MMP9 network in the context of cardiac injury. Gene knockout mouse models have been instrumental in revealing these functions, providing insights into potential therapeutic targets for stroke-related BBB injury and cardiac injury post-myocardial infarction.

References:

1. Li, Wenlu, Shi, Jingfei, Yu, Zhanyang, Wainger, Brian J, Lo, Eng H. 2024. SLC22A17 as a Cell Death-Linked Regulator of Tight Junctions in Cerebral Ischemia. In Stroke, 55, 1650-1659. doi:10.1161/STROKEAHA.124.046736. https://pubmed.ncbi.nlm.nih.gov/38738428/

2. Thévenod, Frank, Herbrechter, Robin, Schlabs, Carolin, Wolff, Natascha A, Roussa, Eleni. 2023. Role of the SLC22A17/lipocalin-2 receptor in renal endocytosis of proteins/metalloproteins: a focus on iron- and cadmium-binding proteins. In American journal of physiology. Renal physiology, 325, F564-F577. doi:10.1152/ajprenal.00020.2023. https://pubmed.ncbi.nlm.nih.gov/37589051/

3. Lavoro, Alessandro, Falzone, Luca, Gattuso, Giuseppe, Libra, Massimo, Candido, Saverio. 2024. Identification of SLC22A17 DNA methylation hotspot as a potential biomarker in cutaneous melanoma. In Journal of translational medicine, 22, 887. doi:10.1186/s12967-024-05622-9. https://pubmed.ncbi.nlm.nih.gov/39358721/

4. Liu, Yan, Shao, Yi-Hui, Zhang, Jun-Meng, Du, Jie, Li, Yu-Lin. 2023. Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression. In Signal transduction and targeted therapy, 8, 394. doi:10.1038/s41392-023-01635-w. https://pubmed.ncbi.nlm.nih.gov/37828006/

5. Candido, Saverio, Tomasello, Barbara, Lavoro, Alessandro, McCubrey, James A, Libra, Massimo. 2022. Bioinformatic analysis of the LCN2-SLC22A17-MMP9 network in cancer: The role of DNA methylation in the modulation of tumor microenvironment. In Frontiers in cell and developmental biology, 10, 945586. doi:10.3389/fcell.2022.945586. https://pubmed.ncbi.nlm.nih.gov/36211450/