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Special Issue "Hematopoietic Serine Proteases: Important Players in Inflammation and Tissue Homeostasis"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 30 June 2020.

Special Issue Editor

Prof. Lars Hellman
E-Mail Website
Guest Editor
Uppsala Biomedicinska Centrum, Uppsala, Sweden
Interests: mast cells; basophilic leukocytes, neutrophilic leukocytes; serine proteases; cleavage specificity; phage display; IgE; evolution; allergy; vaccines; Fc receptors; dermatitis; cytokines; immune regulation

Special Issue Information

Dear Colleagues,

Several of the hematopoietic cell lineages store massive amounts of serine proteases in cytoplasmic secretory granules. These proteases, which can account for up to 35% of the total cellular protein, are stored in an active form, ready for rapid release upon cell activation. In mammals, these proteases are expressed primarily by mast cells, neutrophils, cytotoxic T cells, and NK cells and they are encoded from four different chromosomal loci. Known functions involve activation of apoptosis in target cells, inducing cytokine production, regulating blood pressure, inactivating snake and scorpion toxins, regulating coagulation, regulating cytokine activity as well as participating in tissue homeostasis. Some of them are very active and have a relatively broad specificity and thereby many potential targets, whereas others are highly specific with only one or a few selected targets. Although much is known about these proteases, very much remains unknown. A few examples of important unsolved questions are: why do mast cells continuously produce such high amounts of these proteases; another is the major target for one of the recently identified highly specific neutrophil proteases (NSP4); and what is the prime function of the most highly conserved members of this subfamily of serine proteases (the granzymes A and K)? This Special Issue will try to address some of these important outstanding questions in the area of hematopoietic serine proteases.

Prof. Lars Hellman
Guest Editor

Manuscript Submission Information

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Keywords

  • serine protease
  • cleavage specificity
  • mast cell
  • neutrophilic granulocyte
  • cytotoxic T cell
  • NK cell
  • immune regulation
  • toxin
  • tissue homeostasis
  • angiotensin
  • cytokines

Published Papers (3 papers)

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Research

Open AccessCommunication
Potent and Broad but not Unselective Cleavage of Cytokines and Chemokines by Human Neutrophil Elastase and Proteinase 3
Int. J. Mol. Sci. 2020, 21(2), 651; https://doi.org/10.3390/ijms21020651 - 19 Jan 2020
Abstract
In two recent studies we have shown that three of the most abundant human hematopoietic serine proteases—mast cell chymase, mast cell tryptase and neutrophil cathepsin G—show a highly selective cleavage of cytokines and chemokines with a strong preference for a few alarmins, including [...] Read more.
In two recent studies we have shown that three of the most abundant human hematopoietic serine proteases—mast cell chymase, mast cell tryptase and neutrophil cathepsin G—show a highly selective cleavage of cytokines and chemokines with a strong preference for a few alarmins, including IL-18, TSLP and IL-33. To determine if this is a general pattern for many of the hematopoietic serine proteases we have analyzed the human neutrophil elastase (hNE) and human proteinase 3 (hPR-3) for their cleavage of a panel of 69 different human cytokines and chemokines. Our results showed that these two latter enzymes, in sharp contrast to the two previous, had a very potent and relatively unrestrictive cleavage on this panel of targets. Almost all of these proteins were cleaved and many of them were fully degraded. In light of the proteases abundance and their colocalization, it is likely that together they have a very potent degrading activity on almost any protein in the area of neutrophil activation and granule release, including both foreign bacterial or viral proteins as well as various self-proteins in the area of inflammation/infection. However, a few very interesting exceptions to this pattern were found indicating a high resistance to degradation of some cytokines and chemokines, including TNF-α, IL-5, M-CSF, Rantes, IL-8 and MCP-1. All of these are either important for monocyte-macrophage, neutrophil or eosinophil proliferation, recruitment and activation, suggesting that cytokines/chemokines and proteases may have coevolved to not block the recruitment of monocytes–macrophages, neutrophils and possibly eosinophils during an inflammatory response involving neutrophil activation. Full article
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Open AccessArticle
Extended Cleavage Specificities of Two Mast Cell Chymase-Related Proteases and One Granzyme B-Like Protease from the Platypus, a Monotreme
Int. J. Mol. Sci. 2020, 21(1), 319; https://doi.org/10.3390/ijms21010319 - 02 Jan 2020
Abstract
Mast cells (MCs) are inflammatory cells primarily found in tissues in close contact with the external environment, such as the skin and the intestinal mucosa. They store large amounts of active components in cytoplasmic granules, ready for rapid release. The major protein content [...] Read more.
Mast cells (MCs) are inflammatory cells primarily found in tissues in close contact with the external environment, such as the skin and the intestinal mucosa. They store large amounts of active components in cytoplasmic granules, ready for rapid release. The major protein content of these granules is proteases, which can account for up to 35 % of the total cellular protein. Depending on their primary cleavage specificity, they can generally be subdivided into chymases and tryptases. Here we present the extended cleavage specificities of two such proteases from the platypus. Both of them show an extended chymotrypsin-like specificity almost identical to other mammalian MC chymases. This suggests that MC chymotryptic enzymes have been conserved, both in structure and extended cleavage specificity, for more than 200 million years, indicating major functions in MC-dependent physiological processes. We have also studied a third closely related protease, originating from the same chymase locus whose cleavage specificity is closely related to the apoptosis-inducing protease from cytotoxic T cells, granzyme B. The presence of both a chymase and granzyme B in all studied mammals indicates that these two proteases bordering the locus are the founding members of this locus. Full article
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Open AccessArticle
Extended Cleavage Specificities of Rabbit and Guinea Pig Mast Cell Chymases: Two Highly Specific Leu-Ases
Int. J. Mol. Sci. 2019, 20(24), 6340; https://doi.org/10.3390/ijms20246340 - 16 Dec 2019
Cited by 1
Abstract
Serine proteases constitute the major protein content of mast cell (MC) secretory granules. These proteases can generally be subdivided into chymases and tryptases based on their primary cleavage specificity. Here, we presented the extended cleavage specificities of a rabbit β-chymase and a guinea [...] Read more.
Serine proteases constitute the major protein content of mast cell (MC) secretory granules. These proteases can generally be subdivided into chymases and tryptases based on their primary cleavage specificity. Here, we presented the extended cleavage specificities of a rabbit β-chymase and a guinea pig α-chymase. Analyses by phage display screening and a panel of recombinant substrates showed a marked similarity in catalytic activity between the enzymes, both being strict Leu-ases (cleaving on the carboxyl side of Leu). Amino acid sequence alignment of a panel of mammalian chymotryptic MC proteases and 3D structural modeling identified an unusual residue in the rabbit enzyme at position 216 (Thr instead of more common Gly), which is most likely critical for the Leu-ase specificity. Almost all mammals studied, except rabbit and guinea pig, express classical chymotryptic enzymes with similarly extended specificities, indicating an important role of chymase in MC biology. The rabbit and guinea pig are the only two mammalian species currently known to lack a classical MC chymase. Key questions are now how this major difference affects their MC function, and if genes of other loci can rescue the loss of a chymotryptic activity in MCs of these two species. Full article
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