Nitric oxide (NO) is a free radical molecule expressed in some dendritic cells (DCs) and related cells in the intestine and involved in intestinal immunoglobulin A (IgA) synthesis. It is synthesized from L-arginine by three different isoforms of NO synthase (NOS): neuronal NOS (encoded by NOS1), inducible NOS (iNOS, encoded by NOS2), and endothelial NOS (encoded by NOS3). NO exhibits neurotransmitter, immunomodulator, and vasodilator properties, and exerts effects through two pathways: heme iron- and S-nitrosylation. In the heme iron pathway, NO activates soluble guanylate cyclase (sGC), which converts guanosine monophosphate (GMP) into cyclic GMP, a second messenger that activates protein kinase G. In the S-nitrosylation pathway, NO controls the activity of various intracellular signaling molecules, including enzymes and transcription factors, through S-nitrosylation of the cysteine thiol group.
NO in Homeostatic Inflammation
In the context of homeostatic inflammation, the role of NO becomes very relevant. Inducible Nitric Oxide Synthase (iNOS), which is produced within dendritic cells and macrophages, plays a significant role in this context. When exposed to bacterial elements and inflammatory cytokines, iNOS facilitates the production of large amounts of NO. This production of NO is highly effective in killing bacteria. Looking closer at the gut-associated lymphoid tissue (GALT), there is continuous stimulation by harmless resident bacteria, which triggers iNOS expression and subsequently leads to NO production within the dendritic cells. This phenomenon, known as "homeostatic inflammation", is vital for the production of IgA.
NO's Role in IgA Synthesis
NO has been found to participate actively in both T cell-dependent (TD) and T cell-independent (TI) pathways of IgA synthesis. Specifically, in the TD pathway, NO helps trigger the manifestation of the type II TGF-β receptor on B cells, hence encouraging the production of IgA. In the TI pathway, NO induces the expression of special proteins, BAFF and APRIL, both critical for the development of IgA+ B cells. These proteins are produced by certain cells (CX3CR1+) when triggered by NO. They further facilitate the transformation of IgM+ B cells into IgA+ B cells, whose next step is to evolve into IgA-producing plasma cells. Moreover, NO also has an influence on DC cell migration towards the mesenteric lymph nodes, by stimulating CCR7 induction, and the activation of the TGF-β process through TNF-α induction. Both are crucial steps in IgA synthesis.
Fig 1. NO in TD IgA production.1
In summary, NO has a central role in IgA synthesis, influencing a variety of immune response factors, such as B cell differentiation, BAFF and APRIL production, as well as increasing DC cell mobility and activation. Future studies are necessary to understand more comprehensively the exact mechanisms and functions of NO in IgA production and mucosal immunity. At Creative Biolabs, our team of professionals provides a wide range of non-IgG antibody development services to clients around the globe. In addition, we can cater to your specific needs by providing a full range of IgA antibodies from diverse species including rat, mouse, human, and bovine for a variety of applications. Feel free to contact us for more information.
Reference
- Tezuka, Hiroyuki, and Toshiaki Ohteki. "Regulation of IgA production by intestinal dendritic cells and related cells." Frontiers in immunology 10 (2019): 1891.
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