Nitric oxide modulation in neuroinflammation and the role of mesenchymal stem cells

Abstract

Nitric oxide is a versatile mediator formed by enzymes called nitric oxide synthases. It has numerous homeostatic functions and important roles in inflammation. Within the inflamed brain, microglia and astrocytes produce large amounts of nitric oxide during inflammation. Excessive nitric oxide causes neuronal toxicity and death and mesenchymal stem cells can be used as an approach to limit the neuronal damage caused by neuroinflammation. Mesenchymal stem cell therapy ameliorates inflammation and neuronal damage in disease models of Alzheimer's disease, Parkinson's disease, and other neuroinflammatory disorders. Interestingly, we have reported that in vitro, mesenchymal stem cells themselves contribute to a rise in nitric oxide levels through microglial cues. This may be an undesirable effect and highlights a possible need to explore acellular approaches for mesenchymal stem cell therapy in the central nervous system.

Keywords: Nitric oxide; mesenchymal stem cells; microglia; neurodegenerative diseases; neuroinflammation.

Figure 1.

A graphical summary of the review. (1) In response to homeostatic changes in the brain, microglia are activated to express iNOS. NO is formed when iNOS converts L-arginine to L-citrulline. High levels of NO produced during inflammation increases neurotoxicity, causing neuronal damage. (2) MSCs also produce NO in the inflammatory milieu. Although MSCs are immunosuppressive and downregulate inflammation in the brain, their NO production may contribute to neurotoxicity. (3) Using acellular components from MSCs, can the immunosuppressive properties of MSCs be isolated from their NO production to confer neuroprotection via inhibition of glial iNOS? L-Arg: L-arginine; L-Cit: L-citrulline; NO: nitric oxide; iNOS: inducible nitric oxide synthase. (Graphics created with BioRender.com A color version of this figure is available in the online journal.)