Figure 6. Schematic representation of the role of iron in MWCNT degradation mechanism in macrophages.

. After phagocytosis of CNTs, NOX₂ complex is activated both on cytosolic and phagosomal membranes. Active NOX₂ complex induced O₂^•− production. O₂^•− is turned into H₂O₂ by SOD into phagosome, and H₂O₂ is turned into OH^• in the presence of Fe³⁺ through the Haber-Weiss reaction. OH^• radicals then attack CNTs to generate carboxylic acids that create holes in the graphitic structure as we previously described¹⁸. (a) In the absence of iron embedded into the CNT structure, iron used for Haber-Weiss reaction has to be produced by the cells. Thus, oxidative stress products like H₂O₂ induce Keap1 cysteine oxidation and free Nrf2 for nuclear translocation. FerH and Hmox1 proteins, induced by Nrf2, will be translated for iron production. (b) In the presence of iron filled CNTs, iron from xenobiotics are converted into Fe²⁺ and Fe³⁺ in the acidic environment of the phagosome. Excess of iron ions inhibit heme entry in the cells and so induce Bach1 nuclear translocation and FerH and Hmox1 repression. As iNOS was induced only after Fe@MWCNT exposure, it is likely that Keap1 cysteine will be oxidized by NO^•.