Eicosanoids derive mainly from the membrane-associated fatty acid arachidonic acid. This is cleaved from membrane phospholipids by phospholipase A2, which is activated at the plasma membrane as a result of cell activation. Arachidonic acid can be modified by either of two pathways to give rise to lipid mediators. Modification via the cyclooxygenase pathway produces the prostaglandins and thromboxanes, whereas leukotrienes are produced via the lipoxygenase pathway. Prostaglandin D2 is the major prostaglandin produced by mast cells and recruits TH2 cells, eosinophils, and basophils, all of which express its receptor (PTGDR). Prostaglandin D2 is critical to the development of allergic diseases such as asthma, and polymorphisms in the PTGDR gene have been linked to an increased risk of developing asthma. The leukotrienes, especially C4, D4, and E4, are also important in sustaining inflammatory responses in tissues. Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen exert their effects by preventing prostaglandin production. They inhibit the cyclooxygenases that act on arachidonic acid to form the ring structure present in prostaglandins.
Large amounts of the cytokine tumor necrosis factor (TNF)-α are also released by mast cells after activation. Some comes from stores in the granules; some is newly synthesized by the activated mast cells. TNF-α activates endothelial cells, resulting in increased expression of adhesion molecules, which in turn promotes the influx of pro-inflammatory leukocytes and lymphocytes into the affected tissue (see Chapter 3). Additionally, mast-cell TNF-α contributes importantly to the influx of leukocytes into regional lymph nodes in response to microbial infection of peripheral tissues.
Through the action of all of these mediators, IgE-mediated mast-cell activation orchestrates a broad inflammatory cascade that is amplified by the recruitment of several types of leukocytes including eosinophils, basophils, TH2 lymphocytes, and B cells. The biological role of this reaction in normal host immunity is as a defense against parasite infection (see Section 10-25). In an allergic reaction, however, the acute and chronic inflammatory reactions triggered by mast-cell activation have important pathophysiological consequences, as seen in the diseases associated with allergic responses to environmental antigens. The role of mast cells is not, however, limited to IgE-driven pro-inflammatory responses. Increasingly, mast cells are also considered to have a role in immunoregulation. They can be stimulated by neuropeptides such as substance P and by TLR ligands. In response to multiple stimuli, they can secrete the immunosuppressive cytokine IL-10, suppressing
Fig. 14.10 Eosinophils secrete a range of highly toxic granule proteins and other inflammatory mediators. As for mast cells (see Fig. 14.9), enzymes and toxic mediators released by eosinophils are largely stored preformed in granules. In contrast, cytokines, chemokines, and lipid mediators are largely synthesized after eosinophil activation.
T-cell responses. Conversely, interactions between mast cells and regulatory T cells can prevent mast-cell degranulation.
14-8 Eosinophils and basophils cause inflammation and tissue damage in allergic reactions.