Trends in Immunology
Volume 24, Issue 4, April 2003, Pages 158-161
Journal home page for Trends in Immunology

Research Focus
Tryptase, a novel link between allergic inflammation and fibrosis

https://doi.org/10.1016/S1471-4906(03)00058-9Get rights and content

Abstract

Allergy is a complex inflammatory disease, the etiology of which is well defined. It has recently been proposed that eosinophil, mast-cell and fibroblast interactions contribute to allergy perpetuation. Moreover, mast-cell-derived tryptase might act as a link among these cells. This hypothesis is supported by two recent papers that show that tryptase, seemingly through the protease-activated receptor-2, mediates eosinophil infiltration in the airways and fibroblast proliferation that depends on both cyclooxygenase and prostaglandin synthesis.

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.

References (24)

  • V. Temkin

    Tryptase activates the mitogen-activated protein kinase/activator protein-1 pathway in human peripheral-blood eosinophils, causing cytokine production and release

    J. Immunol.

    (2002)
  • Piliponsky, A.M., et al. Non-IgE dependent activation of human lung and cord blood-derived mast cells is induced by...
  • Cited by (88)

    • Eosinophils, Mast Cells and Basophils

      2022, Comprehensive Pharmacology
    • Mast cells in kidney regeneration

      2021, Regenerative Nephrology
    • Interleukin-17: Friend or foe in organ fibrosis

      2019, Cytokine
      Citation Excerpt :

      Accordingly, depletion of macrophages or mice deficient in MCP1 or CCR2 (mice unable to recruit monocytes/macrophages at the site of inflammation) display protective phenotypes in numerous fibrotic conditions [5,6]. Mast cells secrete tryptases which contribute to connective tissue breakdown and indirectly induce fibroblast proliferation through the synthesis of cyclooxygenase and prostaglandins [7,8]. In contrast, natural killer (NK) cells display predominantly antifibrotic properties in several fibrosis model systems.

    • Fibrotic Response to Biomaterials and all Associated Sequence of Fibrosis

      2015, Host Response to Biomaterials: The Impact of Host Response on Biomaterial Selection
    View all citing articles on Scopus
    View full text