Mast cells promote homeostasis by limiting endothelin-1-induced toxicity

Abstract

Endothelin-1 (ET-1) is a 21-amino-acid peptide, derived from vascular endothelial cells, with potent vasoconstrictor activity. ET-1 has been implicated in diverse physiological or pathological processes, including the vascular changes associated with sepsis. However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood. Both the pathology associated with certain allergic and autoimmune disorders, and optimal host defence against bacterial and parasitic infections are mediated by mast cells. In vitro, mast cells can produce ET-1 (ref. 11), undergo ET-1-dependent and endothelin-A receptor (ET(A))-dependent activation, and release proteases that degrade ET-1 (ref. 14). Although the potential relationships between mast cells and the ET-1 system thus may be complex, the importance of interactions between ET-1 and mast cells in vivo is obscure. Here we show that ET(A)-dependent mast-cell activation can diminish both ET-1 levels and ET-1-induced pathology in vivo, and also can contribute to optimal survival during acute bacterial peritonitis. These findings identify a new biological function for mast cells: promotion of homeostasis by limiting the toxicity associated with an endogenous mediator.

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

“…Thus, in this model, the development of an aspect of the humoral component of the immune response to hapten challenge (the antigen-specific IgG 1 ) results in the generation of a signal (the antigen-IgG 1 immune complexes) that promotes an anti-inflammatory phenotype in the mast cells that are resident at the site of the local reaction (Figure 3h). The notion that mast cells might first promote the sensitization and/or elicitation phases of an immune response, and then help to limit or resolve the local tissue changes induced by antigen challenge, is consistent with the hypothesis that a key function of mast cells is to promote homeostasiseven in instances when mast cells also have a major role in perturbing homeostasis in order to promote host defence [8][9][10][11] .…”

“…Mast cells represent potential sources of many mediators that can enhance or suppress the development, survival, proliferation, migration, maturation, or function of immune cells (reviewed in REFS [1][2][3][5][6][7][8]13,[16][17][18]21,30,31,43,44,[46][47][48][49][50][51][52][53][54][55][56]. Some individual mediators, such as histamine, can have both positive and negative immunomodulatory effects.…”

“…Such 'effector functions' of mast cells include killing pathogens 2,3,7 , degrading potentially toxic endogenous peptides [8][9][10] or components of venoms 9,11 , and regulating the numbers, viability, distribution, phenotype or 'non-immune' functions of structural cells, such as fibroblasts and vascular endothelial cells. Mast cells can exert their effector functions through the direct or indirect actions of a wide spectrum of mast-cell-derived products, and such effects can be observed in both innate [1][2][3]12 and acquired 1,5,6,12,13 immune responses (BOX 1).…”

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

“…However, myocardial TNF-␣ was still elevated on day 5 in the untreated fistula, whereas ET-1 levels were similar to that in bosentan-treated fistula hearts. This reduction in ET-1 levels in the untreated-fistula group on day 5 could possibly be accounted for by the similar findings of Maurer et al (28) and Metsarinne et al (30), demonstrating that the ET-1 peptide was sensitive to chymase-mediated degradation. The sustained mast cell activation reflected by increased MMP activity would be expected to produce increased chymase levels at the 5-day time point in the fistula model (3,4).…”

Lipopolysaccharide-Mediated Mast Cell Activation Induces IFN-γ Secretion by NK Cells

“…However, with the detection of a vast array of cytokines and receptors that are produced, expressed, and/or released by MCs, many new biological functions have been attributed to their activation (1,2). In particular, their essential function in innate immune responses has been shown by various groups (3)(4)(5)(6)(7)(8)(9). Activation of MCs in this context can be mediated via pattern recognition receptors such as TLR3, -4, and -9 (9)(10)(11)(12)(13)(14).…”