Figure 6

Causality for iron-mediated activation of ADAM17, sCD163 and inflammation. (A) Percentage frequency of CD163 + and CD163⁺, TNF-α⁺ in THP1 cells (n = 3) stimulated by Iron/Fenton (50 uM) under ADAM17 inhibition. (*p < 0.05) (B) Cell supernatant level of sCD163 and TNF-α + inTHP1 cells (n = 3) stimulated by Iron/Fenton (50 uM) under ADAM17 inhibition. (*p < 0.05) (C) Expression of genes linked to inflammation, iron regulation and macrophage iron regulation inTHP1 cells stimulated by Iron/Fenton (50 uM) under ADAM17 inhibition. (D) Soluble TNFR1 and TNFR2 levels in the cell supernatant of THP1 macrophages under iron/Fenton stress treated with or without ADAM17 inhibitor (TAPI-1) (*p < 0.05). (E) Percentage frequency of Total TNF-α positive THP1 macrophages under iron/Fenton stress treated with or without ADAM17 inhibitor (TAPI-1) (*p < 0.05). (F) Paradigm for iron-stress, metalloprotease activation and induction of inflammatory cascade in SAH patients: Iron loading in macrophage is by increased expression of iron import receptor (TFR2, DMT1) and secondary iron load contributors (CD163, HMOX1). Iron overload induces peroxide stress and expression of genes linked to iron homeostasis (hepcidin, ferritin, transferrin), oxidative stress (NOX1, NOXA1) and inflammation (TNF-α, ADAM17). Increased expression of ADAM17 increases sCD163 and TNF-α in circulation, which correlates to mortality in SAH patients. Iron chelation and ADAM17 inhibition remarkably neutralizes these alteration and could be used as attractive therapeutic option in such patients. Pathways marked with [***] is significantly increased in SAH patients particularly in those with iron-load.