A proposed model for S100A9-dependent granuloma formation. The neutrophil S100A9 protein may play essential roles in multiple steps of granuloma formation, including the recruitment of neutrophils from peripheral blood (step 1) and the construction of a niche for the development of a granuloma (step 2). S100A9 released from neutrophils stimulates neutrophils and macrophages in autocrine (U-shaped arrows in red) and paracrine (straight arrows in orange) manners, thereby augmenting focal cellular responses via the secretion of proinflammatory cytokines and macrophage-recruiting chemokines as well as other inflammatory mediators. Prolonged focal inflammation with S100A9⁺ neutrophils at the core may contribute to the concentric expansion of the surrounding macrophage layer, resulting in the formation of organized granulomas (step 3). Chronic exposure to S100A9 deposited in the central area of granulomas, as well as the hypoxic and acidic microenvironments, may be highly stressful to cells, potentially serving to generate exhausted (degranulated) neutrophils and central necrosis.