FIGURE 4.

Neutrophils contribute to pathology of autoinflammatory and autoimmune diseases. A key driver of autoinflammation is IL‐1β, a cytokine that potently stimulates neutrophil survival and activity. Neutrophils can also contribute to the production of IL‐1β, thus creating an inflammatory positive feedback loop. Increased IL‐1β signaling prompts activated neutrophils to perpetuate autoinflammation through effector functions and cytokine release. In autoimmunity, neutrophils enhance activation of self‐reactive adaptive immune cells, especially T helper 17 (Th17) cells driving type 3 immune diseases. Thus, immune complexes exposed upon NET formation can stimulate plasmacytoid dendritic cells (pDCs) via endosomal Toll‐like receptors (TLRs) to produce type I interferons (IFN‐I). This, in turn, leads to IL‐23 release by conventional DCs (cDCs) and subsequent priming of Th17 cells. Neutrophils can also facilitate autoantibody production since they release various autoantigens upon activation, through degranulation, ROS production, and NET release. Both Th17 cells and autoantibodies can further activate neutrophils and cause tissue pathology.