Derived from CD34+ multipotent hematopoietic progenitors in the bone marrow under the regulation of stem cell factor (SCF) and IL-3, mast cells circulate in the blood as an immature form, and then migrate and differentiate into tissue specific resident mast cells. Mast cells are present in most tissues characteristically surrounding blood vessels and nerves, and are especially prominent in tissues that form the large host barriers, such as the skin, mucosa of the lungs and intestine, as well as the mouth, conjunctiva and nose. Mast cell phenotype can be influenced by micro-environmental factors, they customize to perform functions specific to the dedicated region. Mast cell activation results in increased fluid secretion and peristalsis in gastrointestinal tract, decreased diameter and increased mucus secretion in airways, increased blood flow and vessel permeability in blood vessels.
The activation pattern of mast cells is determined by types and amounts of signals. Cross-linking of antigen and IgE stimulates mast cells degranulation with a rapid release of stored mediators and sustained production of cytokines, while toll ligands activate mast cells to secret cytokines, chemokines with little or no degranulation. Although many of mast cell derived mediators have proinflammatory effects, others can have anti-inflammation effects, or promote tissue remodeling or repair.
The molecules released by mast cells into the extracellular environment can be classified into small molecule mediators (histamine, serotonin), protein mediators (cytokines, proteases), lipid mediators (leukotrienes, prostaglandins) and proteoglycans (heparin, etc.). Some of them such as histamine, proteases, and proteoglycans are preformed and stored in granules that can be released within seconds, lipid mediators are generated from phospholipids, while most cytokines are de novo synthesized within minutes to hours upon activation.
Mast cell activation
Mast cells can act as either effector cells or regulatory cells in immune responses. Their flexibility is also reflected by the various stimuli pattern through expressing multiple types of receptors and releasing various mediators after activation.
Preformed mediators in granules. The release of preformed mediators in secretory granules is called degranulation, which occurs within seconds upon stimulation and the rapid phase is complete within 5-10 minutes. Histamine, the main mediator of rapid response to mast cell activation, is sequestered to granules by proteoglycans such as heparin. Acting through four G protein-coupled histamine receptors, histamine can increase vascular permeability, and leads to vasodilation and bronchial constriction. Mast cell proteases constitute up to 50% of the cell protein content, and display heterogeneous ex
Eicosanoids. The eicosanoids, including leukotriene (LT) C4, LTB4, prostaglandin D2, and prostaglandin (PG) E2, are generated from the mast cell membrane phospholipids upon stimulation and quickly released concurrently with preformed mediators. Once be activated, phospholipase (PL) A2 hydrolyses phospholipids, producing free arachidonic acid. This is then metabolized, generating LTs and PGs. Eicosanoids can cause bronchoconstriction, immunosuppression and enhance vascular permeability.
Cytokines and chemokines. Mast cells secrete various cytokines (IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, IL-33, GM-CSF and TNF) and chemokines (CCL2, CCL3, CCL5 and CXCL8). Different with preformed granular mediators, cytokines and chemokines are de novo synthesized upon activation, and are released several hours later.
The role of linker for activation of T cells (LAT) in mediating mast cell cytokines and chemokines mRNA and protein ex
By wortmannin (PI3K inhibitor) treatment or p110 null mutation, PI3K has also been shown to regulate FcRI-mediated generation of cytokines in mast cells. PI3K activation recruits PDK1 to the cell membrane, where PDK1 further activates Akt. Akt phosphorylates NFB inhibitor IB, resulting in NFB activation. Moreover, through enhancing PLC, PI3K might activate transcription factor NFAT to regulate cytokine production.