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) from L-arginine, and the NO produced can have both beneficial and detrimental effects. The regulation of NOS2 expression is complex, with cyclic AMP being a modulator that can have stimulatory or inhibitory effects on its expression depending on the cell type [5].

In mouse models, Nos2-/-mice infected with Mycobacterium tuberculosis develop neurobehavioral changes and immunopathology similar to human central nervous system tuberculosis, suggesting that Nos2 deficiency can lead to more severe disease phenotypes in this context [6]. In inflammatory macrophages, LACC1 bridges NOS2 and polyamine metabolism, with LACC1 phenotypes requiring upstream NOS2 [1]. In cancer, while NOS2 was initially thought to be an antitumor component, recent data show that its expression in cancer cells often predicts poor outcome, as it mediates multiple oncogenic pathways [2]. In psoriasis, IL-17 induces NOS2 and fine-tunes its translation, and lower levels of NO drive psoriasis pathogenesis [3]. In myoblasts, disrupted NOS2 metabolism drives the response to wasting-associated cytokines, and NOS2 inhibition can rescue wasting phenotypes [4].

In conclusion, Nos2 is crucial in inflammation, immunity, and disease development. Gene knockout mouse models have been instrumental in revealing its roles in various disease areas such as central nervous system tuberculosis, psoriasis, cancer, and muscle wasting conditions. Understanding the functions of Nos2 provides insights into disease mechanisms and potential therapeutic targets.

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. 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/

3. 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/

4. Arneson-Wissink, Paige C, Doles, Jason D. 2021. Disrupted NOS2 metabolism drives myoblast response to wasting-associated cytokines. In Experimental cell research, 407, 112779. doi:10.1016/j.yexcr.2021.112779. https://pubmed.ncbi.nlm.nih.gov/34428455/

5. 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/

6. 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/