NOS2 gene

The NOS2 gene (NOS2 stands for: Nitric Oxide Synthase 2 which is located on chromosome 17q11.2) codes for the inducible nitric oxide synthase which is expressed in the liver of the lung and bone marrow and is inducible by a combination of lipopolysaccharide and certain cytokines. This enzyme is inducible by a combination of lipopolysaccharide and certain cytokines.three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. an important paralog of this gene is NOS1.

Nitric oxide synthase produces nitric oxide (NO), a messenger molecule with multiple functions throughout the body. Inducible nitric oxide synthase (NOS) is considered a key molecule in immune responses to bacteria, parasites and tumors, and its gene expression is regulated by cytokines (Hokari A et al. 1994).

It has been shown that NO synthesis in normal human airways is due to the continuous expression of the inducible NOS (iNOS) isoform in airway epithelial cells. Although iNOS mRNA expression is abundant in airway epithelial cells, it is not detected in other lung cell types, it has been pointed out that airway epithelial cells are unique in terms of the continuous pattern of iNOS expression in the lung (Guo FH et al. 1995). However, iNOS expression is significantly reduced by inhaled corticosteroids and beta-adrenergic agonists, drugs commonly used to treat inflammatory airway diseases (Guo FH et al. 1995).

Nitric oxide is a reactive free radical that acts as a biological mediator in various processes, including neurotransmission and antimicrobial and antitumor activities. NO also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such as PTGS2/COX2. NO is involved in inflammation (e.g. psoriasis/ Ormerod AD et al. 1998), promotes the synthesis of proinflammatory mediators such as IL6 and IL8 (Jia J et al. 2014).

Biopsies of psoriatic lesions and clinically unaffected skin areas have shown that inducible nitric oxide synthase is not present in normal skin. However, it is clearly upregulated in psoriatic lesion skin, concentrated on keratinocytes, but most strongly in the papillary dermis and to a lesser extent in clinically unaffected psoriatic skin areas. In normal skin, nitric oxide synthase is only expressed in keratinocytes in the granular layer and in eccrine sweat glands. In psoriasis and clinically unaffected skin, however, nitric oxide synthase is present in all layers of the epidermis (Ormerod AD et al. 1998).

The function of Nos2 in mice in immunity against various viruses, bacteria, fungi and parasites is well characterized. Nos2 is important for protective immunity against CMV.

Nitric oxide (NO) can be considered as a "gasotransmitter" that is important for the development of the innate immune response to many bacterial and viral infections and that modulates vascular physiology. The formation of NO through the upregulation of endogenous nitric oxide synthases is an effective method to inhibit viral replication during host defense. It is a future goal to develop gaseous NO, NO prodrugs and NO donor compounds for antiviral therapies (Garren MR et al. 2021).

An autosomal recessive NOS2 deficiency has also been described in mice. Here, the gene coding for nitric oxide synthase 2 (Nos2) is missing. These mice are susceptible to murine CMV infection.

In February 2020, the same autosomal recessive, complete NOS2 deficiency was described in a human. A 51-year-old previously healthy man died after 29 months of progressive CMV infection and respiratory failure due to CMV pneumonia, CMV encephalitis and hemophagocytic lymphohistiocytosis. Exome sequencing of his genomic DNA from blood showed homozygous variants in five genes. The only loss-of-function variant was a homozygous frameshift mutation in nitric oxide synthase 2. This disease is extremely rare, occurring in less than one in a million people.

There are three related pseudogenes in the Smith-Magenis syndrome region on chromosome 17. Alternative splicing of this gene leads to two transcript variants that code for different isoforms.

1. Charles IG et al. (1993) Cloning, characterization, and expression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte. Proc Natl Acad Sci U S A 90:11419-11423.
2. Garren MR et al. (2021) Nitric oxide and viral infection: Recent developments in antiviral therapies and platforms. Appl Mater Today 22:100887.
3. Geller DA et al. (1993) Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci U S A. 90:3491-3495.
4. Guo FH et al. (1995) Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. Proc Natl Acad Sci U S A 92:7809-7813.
5. Hokari A et al. (1994) Cloning and functional expression of human inducible nitric oxide synthase (NOS) cDNA from a glioblastoma cell line A-172. J Biochem 116:575-581.
6. Jia J et al. (2014) Target-selective protein S-nitrosylation by sequence motif recognition. Cell 159:623-634.
7. Ormerod AD et al. (1998) Detection of nitric oxide and nitric oxide synthases in psoriasis. Arch Dermatol Res 290(1-2):3-8
8. Weller R (2003) Nitric oxide: a key mediator in cutaneous physiology. Clin Exp Dermatol 28:511-514.
9. Zhang J et al. (2023) Inducible nitric oxide synthase-expressing myeloid-derived suppressor cells regulated by interleukin 35 contribute to the pathogenesis of psoriasis. Front Immunol 14:1091541.