Mast cells: Tempering toxicity

signaling update home

SOURCE:

Mast cells have a new biological function; they can limit the toxicity and pathology associated with endothelin-1 (ET-1).

A recent report in Nature describes a new biological function for mast cells: limiting the toxicity and pathology associated with endothelin-1 (ET1).

ET1 is a 21-amino-acid peptide with potent vasoconstrictor activity, and it is released by vascular endothelial cells during sepsis and other pathological processes, such as asthma and atherosclerosis. Previous in vitro studies have shown that ET1 induces the activation of mast cells, which triggers the release of proteases that degrade it; however, the involvement of mast cells in the regulation of ET1-associated pathology in vivo is unknown. So, to assess their role in ET1-induced pathology, Maurer et al. gave an intraperitoneal injection of ET1 to wild-type and mast-cell-deficient mice. All mast-cell-deficient mice developed severe hypothermia and diarrhoea, and most died within 3 hours of the injection. By contrast, ET1 injection had no effect on wild-type mice. Restoration of mast cells to the peritoneal cavity of the mutant mice, by adoptive transfer of wild-type mast cells, completely protected the mice from ET1-induced morbidity and mortality.

Using an inhibitor of mast-cell degranulation, BAPTA-AM, the authors next assessed whether degranulation is required for the reduction of ET1-induced toxicity in vivo. When wild-type cells were treated with BAPTA-AM before transfer to mast-cell-deficient mice, the protective effect of the transferred cells was greatly reduced. Further studies identified that chymase, which is released on mast-cell degranulation, is involved in mediating the protective effect by degrading ET1, as wild-type mice that were pretreated with a chymase inhibitor developed hypothermia and diarrhoea after injection of ET1 and had increased amounts of ET1 in the peritoneal cavity compared with untreated mice.

To further explore the mechanism of ET1-induced mast-cell activation, the authors tested the ability of ET1-receptor antagonists to alter the susceptibility of wild-type mice to ET1-induced pathology. Wild-type mice pretreated with an antagonist selective for the ET1 receptor ET_A and then injected with ET1 developed marked hypothermia and diarrhoea, although not to the extent seen in mast-cell-deficient mice, indicating that ET_A has an important role in mediating mast-cell activation. Accordingly, mast-cell-deficient mice that were reconstituted with mast cells that lack expression of ET_A were not protected from ET1-induced hypothermia and diarrhoea, and some mice died. Moreover, in the peritoneal cavity of these mice, mast-cell degranulation was reduced, and ET1 levels were increased compared with those of mice that were reconstituted with wild-type cells, indicating that mast cells limit ET1-associated pathology in vivo by reducing the concentration of the peptide.

Finally, the authors used the caecal ligation and puncture (CLP) model of acute bacterial peritonitis to assess the biological significance of mast-cell-mediated protection from ET1-induced pathology. As expected, the mortality that occurred within 90 hours of CLP was greater in mast-cell-deficient mice than in wild-type mice. However, reconstitution of mast-cell-deficient mice with wild-type cells, but not with ET_A-deficient cells, increased their survival to levels that were similar to those of wild-type mice, indicating that protective mast-cell function in the CLP model involves ET1- and ET_A-dependent mechanisms.

In this study, the authors describe a novel role for mast cells in tempering the toxicity that is induced by endogenous mediators, and they speculate that, in future, mast-cell-dependent mechanisms might also be found to regulate the toxicity of other compounds.

Lucy Bird

References

Maurer, M. et al. Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature 432, 512–516 (2004). | Article | PubMed |