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. 2023 Jan 12;24(2):1526. doi: 10.3390/ijms24021526

Figure 1.

Figure 1

In healthy intestine (left), damage to the intestinal barrier triggers the recruitment of neutrophils from the circulation to the inflamed tissue along a chemotactic gradient formed by cytokines (IL-1β, IL-6, TNF-α), chemokines (CCL8, CXCL10, MIP-2), and growth factors (GM-CSF, G-CSF). Neutrophil recruitment is also mediated by bacteria-derived molecules such as formyl-methionyl-leucyl-phenylalanine (fMLP) and short-chain fatty acids (SCFAs). The recruited neutrophils participate in the elimination of microorganisms through phagocytosis, degranulation, reactive oxygen species (ROS) generation, and the release of neutrophil extracellular traps (NETs). Once their functions are completed, neutrophils undergo apoptosis and efferocytosis, facilitating the resolution of inflammation, tissue repair, and a return to normal tissue homeostasis. The participation of neutrophils and NETs in IBD is a double-edged sword (right). Neutrophils cooperate in wound healing and the resolution of inflammation by releasing vascular endothelial growth factors (VEGFs) and lipid mediators (protectin D1, resolvin E1). These factors impede neutrophil recruitment and promote phagocytosis. NETs impede the spread of microorganisms by trapping them in an environment of microbicidal components and stimulate the healing of the intestinal mucosa. Neutrophils directly cause tissue damage by releasing neutrophil elastase, proteases (MMPs), pro-inflammatory cytokines (IL-8, TNF-α, IL-1β), leukotriene B4, and ROS. These factors provoke not only injury to the epithelial barrier, but also the recruitment of neutrophils and other immune cells to the inflamed tissue. Neutrophil recruitment is also promoted by the cytokines IL-1α, IL-17, IL-22, G-CSF, and GM-CSF. Lack of the IBD protective gene CARD9 in neutrophils enhances ROS generation. IL-8, TNF-α, and PAD4 (increased in UC patients) contribute to NET production. Accumulation of NETs in the colon is accompanied by the induction of tissue damage and inflammation, as NETs also boost TNF-α and IL-1β production. Part of the figure was generated by using pictures from Servier Medical Art.