Dermal nitrite application enhances global nitric oxide availability: new therapeutic potential for immunomodulation?

2 Abstract Nitrite in/on the skin has potent antimicrobial effects and is believed to act as a local nitric oxide (NO) reservoir capable of modulating dermal cell function. Using male Wistar rats we here show that nitrite, when applied in neutral aqueous solution to the skin surface, readily permeates the dermis to reach the systemic circulation and cause widespread nitros(yl)ation of tissue proteins. These events extend to all internal organs investigated including compartments crucial for the regulation of immune cell function such as thymus, spleen and lymph nodes. Using a transgenic mouse model of allergic asthma, we further find that systemic nitrite administration potently suppresses the number of T-cells and other inflammatory cells and the production of the Th2 effector cytokine, IL-13 in the lung. Thus, nitrite formed via reduction of nitrate or oxidation of ammonia on the skin, may exert previously unappreciated systemic effects akin to NO. These observations have the potential to shift the current emphasis of nitrite from cardiovascular pharmacology to immunology. Word count: 76 words (title page) 163 words (abstract) 1134 words (main text without title, abstract and refs) 2645 words (total) 3 TO THE EDITOR Whereas systemic administration of nitrite (NO 2-) affords protection against ischemia/reperfusion-related organ damage (Lundberg et al., 2008), topical nitrite application exerts local antimicrobial effects and promotes wound healing (Weller et al. The latter two actions require acidification, are often accompanied by increased blood flow (Tucker et al., 1999; Gribbe et al., 2008) and thought to be mediated by the formation of nitric oxide (NO), albeit not all effects of nitrite necessarily occur through NO generation (Bryan et al., 2005). While the significance of NO in cutaneous physiology is widely recognized (Bruch-Gerharz et al., 1998; Weller, 2003) relevance and biological function of its oxidation product, nitrite, are incompletely understood (Suschek et al., 2006), as is how dermal nitrite couples to systemic NO/nitrite physiology. Nitrite concentrations in human skin are considerably higher than those in circulation (Paunel et al., 2005; Mowbray et al., 2009) and a reflection of local nitric oxide synthase activity. Nitrite is also a constituent of human sweat, possibly from reduction of nitrate by commensal heterotrophic bacteria colonizing the skin (Weller et al., 1996). The actions of nitrite in/on the skin have been proposed to contribute to host defense against skin pathogens and include modulation of cutaneous T-cell function, keratinocyte differentiation, blood flow, and protection against UV-radiation damage (Weller …