Nos2, also known as inducible nitric oxide synthase (i-NOS), is an enzyme that plays a central role in inflammatory reactions following infection or tissue damage. It catalyzes the production of nitric oxide (NO), which can have both beneficial and detrimental actions. NOS2 is involved in multiple pathways, including immunometabolic signaling, and is important in the mammalian immune system's response to invaders and host damage [1,2,5,6]. Genetic models, such as gene-knockout (KO) mice, are valuable for studying Nos2.

In a mouse model infected with Salmonella enterica Typhimurium, genetic and mechanistic connections were validated among NOS2, LACC1, and ODC1 in bone marrow-derived macrophages. LACC1, highly expressed in inflammatory macrophages, bridges NOS2 and polyamine metabolism by converting L-citrulline to L-ornithine and isocyanic acid, and its phenotypes require upstream NOS2 [1]. In another study, Nos2-/-mice infected with M. tuberculosis developed neurobehavioral changes and immunopathology mimicking human central nervous system tuberculosis, suggesting Nos2 plays a role in CNS-TB pathophysiology [7].

In conclusion, Nos2 is essential in inflammatory responses and immunometabolic signaling. The use of Nos2 KO mouse models has provided insights into its role in diseases such as inflammatory bowel diseases, arthritis, cancer, psoriasis, and central nervous system tuberculosis. These models help us understand the mechanisms underlying these diseases and may contribute to the development of new therapeutic strategies [1,2,3,4,7].

References:

1. Wei, Zheng, Oh, Joonseok, Flavell, Richard A, Crawford, Jason M. 2022. LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages. In Nature, 609, 348-353. doi:10.1038/s41586-022-05111-3. https://pubmed.ncbi.nlm.nih.gov/35978195/

2. Brüne, Bernhard, Courtial, Nadine, Dehne, Nathalie, Syed, Shahzad N, Weigert, Andreas. 2016. Macrophage NOS2 in Tumor Leukocytes. In Antioxidants & redox signaling, 26, 1023-1043. doi:10.1089/ars.2016.6811. https://pubmed.ncbi.nlm.nih.gov/27397579/

3. Thomas, Douglas D, Wink, David A. . NOS2 as an Emergent Player in Progression of Cancer. In Antioxidants & redox signaling, 26, 963-965. doi:10.1089/ars.2016.6835. https://pubmed.ncbi.nlm.nih.gov/28506076/

4. Köhler, Ines, Bivik Eding, Cecilia, Kasic, Nada-Katarina, Verma, Deepti, Enerbäck, Charlotta. 2024. NOS2-derived low levels of NO drive psoriasis pathogenesis. In Cell death & disease, 15, 449. doi:10.1038/s41419-024-06842-z. https://pubmed.ncbi.nlm.nih.gov/38926337/

5. Miranda, Katrina M, Ridnour, Lisa A, Cheng, Robert Y S, Wink, David A, Thomas, Douglas D. . The Chemical Biology of NO that Regulates Oncogenic Signaling and Metabolism: NOS2 and Its Role in Inflammatory Disease. In Critical reviews in oncogenesis, 28, 27-45. doi:10.1615/CritRevOncog.2023047302. https://pubmed.ncbi.nlm.nih.gov/37824385/

6. Galea, E, Feinstein, D L. . Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 13, 2125-37. doi:. https://pubmed.ncbi.nlm.nih.gov/10593859/

7. Poh, Xuan Ying, Hong, Jia Mei, Bai, Chen, Ding, Cristine S L, Ong, Catherine W M. 2022. Nos2-/- mice infected with M. tuberculosis develop neurobehavioral changes and immunopathology mimicking human central nervous system tuberculosis. In Journal of neuroinflammation, 19, 21. doi:10.1186/s12974-022-02387-0. https://pubmed.ncbi.nlm.nih.gov/35073927/