Fig. 5

Molecular models of the potential role of proteins involved in the Nrf2 – mediated response to NCC exposure. a NiSO₄ allows the release of Ni²⁺ ion which increases ROS production in the cytoplasm, inducing 1) hypomethylation and HAT inhibition through increased HDACs and NCoRs activity, which reduces Keap1/Nrf2 dissociation and posterior Nrf2/ARE transcription, and 2) inhibition of DNA repair process; b) Ni₃S₂ uptake is facilitated via phagocytosis, delaying Ni²⁺ dissolution inside the cytoplasm. However both Ni₃S₂ and NiSO₄ releases Ni²⁺ outside alveolar cells increasing production of Ni-protein complexes which acts as antigens for APC cells following differentiation to Ni²⁺-specific interferon γ (IFN-γ)-producing effector T cells, whereas inside the cell increase NF-kB transcription and proinflammatory response; c) Ni₃S₂ is capable of the release of high levels of the Ni²⁺ ion and ROS as a product of Ni₃S₂ mediated-phagocytosis. Retention of Ni₃S₂ and slow dissolution in endosomes are the primary cause of a possible chronic inflammation response. Ni²⁺ from Ni₃S₂ can induce ER stress through the activation of PERK, IRE1, and ATF6 pathways. During ER-stress conditions proteins that fail the ER quality control are transported back to the cytosol where they are rapidly destroyed by the ER-associated degradation (ERAD) pathway. Additionally, redox status generated by Ni²⁺ regulates the nuclear activity of NF-kB proteins by altering the binding of NF-kB proteins to DNA in part via the Nrf2-signaling pathway. The absence of Nrf2 can exacerbate NF-κB activity leading to increased cytokine production