Arg1, also known as arginase 1, is an enzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea, regulating the last step of the urea cycle [2,3,5]. It is involved in multiple biological processes, such as influencing immune cell function, tissue development, and cancer progression [1-3,5-8,10]. Genetic models, especially KO mouse models, have been crucial in understanding its functions.

In stroke mouse models, STAT6/Arg1 signaling axis is important. STAT6 deficiency led to reduced Arg1 expression in microglia/macrophages, impairing efferocytosis, increasing inflammation, and worsening stroke outcomes, suggesting that Arg1 via this axis modulates microglia/macrophage phenotype and inflammation resolution [1]. In the context of cancer, in mouse models of endometrial cancer, high ARG1 expression was associated with poor prognosis [3,5]. In breast cancer, overexpression of ARG1 in cancer cells suppressed cell proliferation, migration, and xenograft tumor growth in mouse models, functioning as a tumor suppressor [4]. For lung fibrosis, macrophage-fibroblast crosstalk induced Arg1 expression in macrophages, and Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used for collagen synthesis [6]. Selective depletion of Arg1-expressing tumor-associated macrophages (Arg1+ TAMs) in a mouse model inhibited tumor growth and reduced the ratio of TH1-Treg cells in the tumor microenvironment [7].

In conclusion, Arg1 is essential in processes like inflammation resolution, tissue development, and cancer regulation. Studies using KO/CKO mouse models have significantly enhanced our understanding of its role in stroke, cancer, and lung fibrosis, offering insights into potential therapeutic targets for these diseases.

References:

1. Cai, Wei, Dai, Xuejiao, Chen, Jie, Hu, Xiaoming, Chen, Jun. 2019. STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke mice. In JCI insight, 4, . doi:10.1172/jci.insight.131355. https://pubmed.ncbi.nlm.nih.gov/31619589/

2. Bin Sawad, Aseel, Jackimiec, John, Bechter, Mark, Uyei, Jennifer, Diaz, George A. 2022. Epidemiology, methods of diagnosis, and clinical management of patients with arginase 1 deficiency (ARG1-D): A systematic review. In Molecular genetics and metabolism, 137, 153-163. doi:10.1016/j.ymgme.2022.08.005. https://pubmed.ncbi.nlm.nih.gov/36049366/

3. Tran, Dinh Nam, Rozen, Valery, Nguyen, Loan Thi Kim, Yoo, Jung-Yoon, Jeong, Jae-Wook. 2024. ARG1 Is a Potential Prognostic Marker in Metastatic Endometrial Cancer. In Reproductive sciences (Thousand Oaks, Calif.), 31, 1632-1641. doi:10.1007/s43032-024-01493-z. https://pubmed.ncbi.nlm.nih.gov/38388922/

4. Ming, Zhengnan, Zou, Zizheng, Cai, Kaimei, Luo, Junli, Luo, Zhiyong. . ARG1 functions as a tumor suppressor in breast cancer. In Acta biochimica et biophysica Sinica, 52, 1257-1264. doi:10.1093/abbs/gmaa116. https://pubmed.ncbi.nlm.nih.gov/33128544/

5. Tran, Dinh Nam, Rozen, Valery, Hunter, Mark I, Kim, Tae Hoon, Jeong, Jae-Wook. 2023. ARG1 is a potential prognostic marker in metastatic and recurrent endometrial cancer. In Research square, , . doi:10.21203/rs.3.rs-2917380/v1. https://pubmed.ncbi.nlm.nih.gov/37503068/

6. Yadav, Preeti, Ortega, Javier Gómez, Tamaki, Whitney, Tharp, Kevin M, Bhattacharya, Mallar. 2024. Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.09.06.556606. https://pubmed.ncbi.nlm.nih.gov/39211079/

7. Kuratani, Ayumi, Okamoto, Masaaki, Kishida, Kazuki, Arase, Hisashi, Yamamoto, Masahiro. 2024. Platelet factor 4-induced TH1-Treg polarization suppresses antitumor immunity. In Science (New York, N.Y.), 386, eadn8608. doi:10.1126/science.adn8608. https://pubmed.ncbi.nlm.nih.gov/39571033/