Proposed model for the proinflammatory response induced by S100A8/PhosphoA9. Neutrophils activated under different stimulatory conditions (PMA, MSU, Aspergillus fumigates, or Aspergillus nidulans) are releasing NETs through a mechanism involving NADPH oxidase, PAD4, NE, and MPO (34). During NET formation, active S100A8/A9 are released in the extracellular space in a phosphorylated form. S100A8/PhosphoA9 can then activate surrounding neutrophils to secrete cytokines (TNFα and IL-6) and chemokines (CCL2, CCL3, CCL4, and CXCL8). This release is mainly regulated through TLR4 signaling pathways, although other receptors (such as RAGE) are involved in S100A8/PhosphoA9-mediated CCL2 secretion. Thus, S100A8/PhosphoA9 released from neutrophils are involved in the amplification of the inflammatory process and could be the hallmark of various inflammatory diseases. MPO, myeloperoxidase; MSU, monosodium urate monohydrate; NE, neutrophil elastase; PAD4, peptidyl arginine deiminase; PMA, phorbol 12-myristoyl 13-acetate; NET, neutrophil extracellular trap; NADPH oxidase, nicotinamide adenine dinucleotide phosphate-oxidase; TNFα, tumor necrosis factor alpha; IL-6, interleukin 6.