Role of Mast Cells in Progressive Renal Diseases (1)
Mast cells are tissue-specific multifunctional cells, with diverse phenotypes in different anatomic sites in various species, collectively referred to as “mast cell heterogeneity.” They are located close to blood vessels, epithelia, and nerves in connective tissues, being strategic sentinels at primary immune barriers. Mast cells activate pathways including complement and signaling through microbial pattern recognition receptors, toll-like receptors (TLR), understanding of a role for mast cells in host defense in other diseases. Complement also activates mast cells, and complement-dependant microbial killing is at least partially dependent on mast cell function for full expression. In animal models, the important synergistic interaction between TLR in mast cells demonstrates upregulated cytokine production and increased survival from bacterial infection.
Mast cells are also important in chronic inflammation with the capacity to produce a range of bioactive amines, proteoglycans, growth hormones, chemokines, and cytokines, which mediate a diverse range of mast cell function.
Mast cells are prominent in tubulointerstitial nephritis associated with progressive fibrosis and renal failure. These include almost all of the primary and secondary forms of glomerulonephritis, diabetic nephropathy, and allograft rejection, as well as amyloid, renovascular ischemia, reflux nephropathy, polycystic kidney disease, and drug-induced nephropathy. Mast cell presence is correlated semiquantitatively with fibrosis, progressive decline in glomerular filtration, and poor outcome. Mast cells elaborate cytokines, chemokines, and leukotrienes recruiting and activating leukocytes. Mast cell degranulation leads to the release of histamine, heparin, and cytokines, in particular IL-4 and TNF-α.
Mast cells have been associated with fibrosis in other organs besides the kidney, including skin, experimental models of lung fibrosis, and scleroderma. The models of homocysteine-induced cardiac remodeling and pancreatic fibrosis showed unexpected outcomes suggesting mast cells protect against the development of fibrosis. Preliminary studies in a murine model of ureteral obstruction also suggested that mast cells protect against fibrosis. Thus, data from experimental mast cell–deficient mice do not support the attractive hypothesis that mast cells play a profibrotic role in chronic renal disease.
Mast cells stimulate the migration of antigen-presenting cells to nodes through the release of IL-1, -3, and -6 and TNF. They also influence T cell differentiation: IL-4 and histamine direct Th2 responses as well as modulate the differentiation of Th17+ CD4 cells. Mast cells also have the potential to act as immunoregulators of adaptive immunity because of their potential to produce TGF-β, IL-4 and -10, and histamine.