Pld2, short for Phospholipase D2, is a major isoform of the PLD family. It is crucial in mediating inflammatory reactions and is involved in regulating cell proliferation, migration, and various pathophysiological processes. Its enzymatic activity regulates the generation of phosphatidic acid (PA), which is involved in multiple signaling pathways [1,2,3,4,5,6,7,8]. Gene knockout models, such as KO mouse models, are valuable tools for studying its functions.

In KO mouse models, PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway [1]. PLD2 deficiency also alleviates endothelial glycocalyx degradation in LPS-induced ARDS/ALI, inhibiting the inflammatory process and protecting against endothelial glycocalyx injury [2]. In adipocytes, Pld2 deletion or PLD2-specific inhibitor treatment augments adaptive thermogenesis by improving mitochondrial quality and quantity, making mice resistant to high-fat-diet-induced obesity, glucose intolerance, and insulin resistance [3]. In an IL-23-driven psoriasiform dermatitis model, PLD2 deficiency significantly reduces psoriasiform inflammation, suggesting its role in psoriasis pathophysiology [5]. In sepsis-induced ALI, PLD2 knockout protects against LPS-induced lung injury by regulating the PA/STAT3 phosphorylation/endothelial TJ axis [6].

In conclusion, PLD2 is essential in multiple biological processes, especially in inflammatory-related diseases. The study of PLD2 through gene knockout mouse models has revealed its role in diseases such as sepsis-induced cardiomyopathy, ARDS/ALI, obesity-related metabolic disorders, and psoriasis. These findings provide potential therapeutic targets for treating these diseases by targeting PLD2.

References:

1. Li, Jun, Teng, Da, Jia, Wenjuan, Wang, Jianxun, Yang, Jun. 2024. PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway. In Inflammation research : official journal of the European Histamine Research Society ... [et al.], 73, 1033-1046. doi:10.1007/s00011-024-01881-w. https://pubmed.ncbi.nlm.nih.gov/38630134/

2. Kong, Guiqing, Li, Dongxiao, Liu, Xiangyong, Qu, Jianyu, Wang, Xiaozhi. 2024. PLD2 deficiency alleviates endothelial glycocalyx degradation in LPS-induced ARDS/ALI. In Biochemical and biophysical research communications, 716, 150019. doi:10.1016/j.bbrc.2024.150019. https://pubmed.ncbi.nlm.nih.gov/38703555/

3. Kim, Hyung Sik, Park, Min Young, Yun, Nam Joo, Koh, Ara, Bae, Yoe-Sik. 2021. Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice. In The Journal of experimental medicine, 219, . doi:10.1084/jem.20211523. https://pubmed.ncbi.nlm.nih.gov/34940790/

4. Muñoz-Galván, Sandra, Verdugo-Sivianes, Eva M, Santos-Pereira, José M, Estevez-García, Purificación, Carnero, Amancio. 2024. Essential role of PLD2 in hypoxia-induced stemness and therapy resistance in ovarian tumors. In Journal of experimental & clinical cancer research : CR, 43, 57. doi:10.1186/s13046-024-02988-y. https://pubmed.ncbi.nlm.nih.gov/38403587/

5. Su, Zhi, Slivka, Peter, Paulsboe, Stephanie, Honore, Prisca, Goedken, Eric R. 2023. Importance of PLD2 in an IL-23 driven psoriasiform dermatitis model and potential link to human psoriasis. In The Journal of dermatology, 50, 1321-1329. doi:10.1111/1346-8138.16899. https://pubmed.ncbi.nlm.nih.gov/37455419/

6. Qian, Tiantian, Qi, Boyang, Fei, Yuxin, Huang, Xiao, Wang, Xiaozhi. 2022. PLD2 deletion alleviates disruption of tight junctions in sepsis-induced ALI by regulating PA/STAT3 phosphorylation pathway. In International immunopharmacology, 114, 109561. doi:10.1016/j.intimp.2022.109561. https://pubmed.ncbi.nlm.nih.gov/36700766/

7. Wang, Fang, Zhang, Jing, Zhou, Gang. 2020. HIF1α/PLD2 axis linked to glycolysis induces T-cell immunity in oral lichen planus. In Biochimica et biophysica acta. General subjects, 1864, 129602. doi:10.1016/j.bbagen.2020.129602. https://pubmed.ncbi.nlm.nih.gov/32205175/

8. Liu, Xuan, Shen, Lei, Wang, Haiyu. 2024. Decreased Expression of PLD2 Promotes EMT in Colorectal Cancer Invasion and Metastasis. In Journal of Cancer, 15, 2981-2993. doi:10.7150/jca.89970. https://pubmed.ncbi.nlm.nih.gov/38706911/