Trends in Immunology
Research FocusTryptase, a novel link between allergic inflammation and fibrosis
Section snippets
Interactions between mast cells and eosinophils
Recent studies suggest that an important cross-talk occurs between mast cells and eosinophils. We have demonstrated that eosinophil survival is enhanced by rat peritoneal mast-cell-derived tumor necrosis factor-α (TNF-α) that induces the autocrine production of granulocyte–monocyte-colony stimulating factor (GM-CSF) 3, 4 (Fig. 1a). Moreover, we have recently shown that mast-cell-derived tryptase is the primary mediator that induces interleukin-6 (IL-6) and IL-8 release in eosinophils by
Allergic inflammation and fibrosis
Asthma is a chronic inflammatory disease often caused by allergy and characterized by epithelial damage and consequently its repair. The chronic presence of these processes has been associated with fibrosis and airway remodeling that in turn could cause irreversible alterations in the anatomy of the airways and probably a progressive decline in lung functions [8].
One of the initial features of airway remodeling in asthma is the fibrotic response in which fibroblasts are one of the main direct
Or fibrosis and allergic inflammation?
It can be implied that there is a linear and perhaps progressive link between inflammation and fibrosis and/or remodeling. However, no consistent evidence provides definitive proof. Indeed, it is more probable that both processes collaborate for their own persistence in advanced stages of the disease. For instance, fibroblasts can modulate mast-cell and eosinophil functionality. The membrane form of stem-cell factor (SCF), the main human mast-cell survival and differentiation factor, is
Tryptase: an ‘arising’ mast-cell mediator
Tryptase constitutes one of the most abundant human mast-cell proteins. There has been a steady increase in tryptase research over the past two decades. This has greatly contributed to the current understanding of its genetics, structure, synthesis, activation, release, substrate preferences, inhibitor susceptibility, biological targets and prospects for therapeutic inhibition. The different human tryptase genes reside on chromosome 16p13.3. This locus contains closely linked genes that encode
Tryptase–PAR2 in allergic inflammation
Animal models have provided strong evidence for the involvement of tryptase in acute and chronic allergic inflammation. Injection of human lung tryptase into the skin of guinea pigs or sheep can provoke mast-cell activation (Fig. 2a) with a consequent increase in microvascular leakage within minutes and a massive accumulation of neutrophils and eosinophils [17].
The relevance of PAR2 (the proposed receptor for tryptase) in airway inflammation has been demonstrated in vivo by Schmidlin et al. who
Tryptase–PAR2 in fibrosis
Tryptase is also a well known mitogenic factor for dog tracheal smooth muscle cells, human smooth muscle cells and human lung and dermal fibroblasts. Both smooth muscle hyperplasia and fibrotic changes contribute to the remodeling process described above [8]. Frungieri et al. [19] have recently proposed a novel mechanism by which mast-cell-derived tryptase induces fibroblast proliferation. This group showed that mast-cell-derived tryptase and the PAR2 agonist peptide SLIGKV induce the
Tryptase–PAR2 as a pharmacologic target
The observations reported would impel us to consider the use of tryptase inhibitors and/or PAR2 antagonists for the suppression of allergic inflammation and/or remodeling processes. Some evidence indicates that the use of selective antagonists for PAR2 might not have the expected therapeutic effect because of possible compensatory responses through PAR1 [21]. By contrast, the therapeutic potential of tryptase inhibitors has already been tested in allergic inflammation models in vivo. For
Conclusions
We have discussed the cross-talk among mast cells, eosinophils and fibroblasts in terms of its importance in the perpetuation of allergic inflammation and in contributing to the fibrosis and/or remodeling process. We have also highlighted novel data on the primary role of tryptase in allergy onset and outcome. Nevertheless, it is evident that the puzzle of allergic inflammation and consequent fibrosis and/or remodeling is still lacking pieces necessary for a complete understanding of the
Acknowledgements
We would like to thank our colleagues from the group of F.L-S. for their contribution of data in this publication.
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