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Hematopoietic Serine Proteases: Important Players in Inflammation and Tissue Homeostasis

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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: closed (31 December 2020) | Viewed by 22933

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Prof. Dr. Lars Hellman

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Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, 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
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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

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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 (7 papers)

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Research

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21 pages, 6142 KiB

Open AccessArticle

Extended Cleavage Specificity of the Rat Vascular Chymase, a Potential Blood Pressure Regulating Enzyme Expressed by Rat Vascular Smooth Muscle Cells

by Petter Berglund, Srinivas Akula, Zhirong Fu, Michael Thorpe and Lars Hellman

Int. J. Mol. Sci. 2020, 21(22), 8546; https://doi.org/10.3390/ijms21228546 - 12 Nov 2020

Cited by 7 | Viewed by 1947

Abstract

Serine proteases constitute the major protein content of the cytoplasmic granules of several hematopoietic cell lineages. These proteases are encoded from four different loci in mammals. One of these loci, the chymase locus, has in rats experienced a massive expansion in the number of functional genes. The human chymase locus encodes 4 proteases, whereas the corresponding locus in rats contains 28 such genes. One of these new genes has changed tissue specificity and has been found to be expressed primarily in vascular smooth muscle cells, and therefore been named rat vascular chymase (RVC). This β-chymase has been claimed to be a potent angiotensin-converting enzyme by cleaving angiotensin (Ang) I into Ang II and thereby having the potential to regulate blood pressure. To further characterize this enzyme, we have used substrate phage display and a panel of recombinant substrates to obtain a detailed quantitative view of its extended cleavage specificity. RVC was found to show a strong preference for Phe and Tyr in the P1 position, but also to accept Leu and Trp in this position. A strong preference for Ser or Arg in the P1’ position, just C-terminally of the cleavage site, and a preference for aliphatic amino acids in most other positions surrounding the cleavage site was also seen. Interesting also was a relatively strict preference for Gly in positions P3’ and P4’. RVC thereby shares similarity in its specificity to the mouse mucosal mast cell chymase mMCP-1, which efficiently converts Ang I to Ang II. This similarity adds support for the role of β-chymases as potent angiotensin converters in rodents, as their α-chymases, which have the capacity to efficiently convert Ang I into Ang II in other mammalian lineages, have become elastases. However, interestingly we found that RVC cleaved both after Arg2 and Phe8 in Ang I. Furthermore this cleavage was more than two hundred times less efficient than the consensus site obtained from the phage display analysis, indicating that RVC has a very low ability to cleave Ang I, raising serious doubts about its role in Ang I conversion. Full article

(This article belongs to the Special Issue Hematopoietic Serine Proteases: Important Players in Inflammation and Tissue Homeostasis)

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18 pages, 3002 KiB

Open AccessArticle

Mast Cells Limit Ear Swelling Independently of the Chymase Mouse Mast Cell Protease 4 in an MC903-Induced Atopic Dermatitis-Like Mouse Model

by Sofie Svanberg, Zhiqiang Li, Pontus Öhlund, Ananya Roy and Magnus Åbrink

Int. J. Mol. Sci. 2020, 21(17), 6311; https://doi.org/10.3390/ijms21176311 - 31 Aug 2020

Cited by 9 | Viewed by 3924

Abstract

Atopic dermatitis (AD) is a complex, often lifelong allergic disease with severe pruritus affecting around 10% of both humans and dogs. To investigate the role of mast cells (MCs) and MC-specific proteases on the immunopathogenesis of AD, a vitamin D₃-analog (MC903) was used to induce clinical AD-like symptoms in c-kit-dependent MC-deficient Wsh^−/− and the MC protease-deficient mMCP-4^−/−, mMCP-6^−/−, and CPA3^−/− mouse strains. MC903-treatment on the ear lobe increased clinical scores and ear-thickening, along with increased MC and granulocyte infiltration and activity, as well as increased levels of interleukin 33 (IL-33) locally and thymic stromal lymphopoietin (TSLP) both locally and systemically. The MC-deficient Wsh^−/− mice showed significantly increased clinical score and ear thickening albeit having lower ear tissue levels of IL-33 and TSLP as well as lower serum levels of TSLP as compared to the WT mice. In contrast, although having significantly increased IL-33 ear tissue levels the chymase-deficient mMCP-4^−/− mice showed similar clinical score, ear thickening, and TSLP levels in ear tissue and serum as the WT mice, whereas mMCP-6 and CPA3 -deficient mice showed a slightly reduced ear thickening and granulocyte infiltration. Our results suggest that MCs promote and control the level of MC903-induced AD-like inflammation. Full article

(This article belongs to the Special Issue Hematopoietic Serine Proteases: Important Players in Inflammation and Tissue Homeostasis)

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12 pages, 2554 KiB

Open AccessArticle

Mast Cell β-Tryptase Is Enzymatically Stabilized by DNA

by Sultan Alanazi, Mirjana Grujic, Maria Lampinen, Ola Rollman, Christian P. Sommerhoff, Gunnar Pejler and Fabio Rabelo Melo

Int. J. Mol. Sci. 2020, 21(14), 5065; https://doi.org/10.3390/ijms21145065 - 17 Jul 2020

Cited by 13 | Viewed by 2967

Abstract

Tryptase is a tetrameric serine protease located within the secretory granules of mast cells. In the secretory granules, tryptase is stored in complex with negatively charged heparin proteoglycans and it is known that heparin is essential for stabilizing the enzymatic activity of tryptase. However, recent findings suggest that enzymatically active tryptase also can be found in the nucleus of murine mast cells, but it is not known how the enzmatic activity of tryptase is maintained in the nuclear milieu. Here we hypothesized that tryptase, as well as being stabilized by heparin, can be stabilized by DNA, the rationale being that the anionic charge of DNA could potentially substitute for that of heparin to execute this function. Indeed, we showed that double-stranded DNA preserved the enzymatic activity of human β-tryptase with a similar efficiency as heparin. In contrast, single-stranded DNA did not have this capacity. We also demonstrated that DNA fragments down to 400 base pairs have tryptase-stabilizing effects equal to that of intact DNA. Further, we showed that DNA-stabilized tryptase was more efficient in degrading nuclear core histones than heparin-stabilized enzyme. Finally, we demonstrated that tryptase, similar to its nuclear localization in murine mast cells, is found within the nucleus of primary human skin mast cells. Altogether, these finding reveal a hitherto unknown mechanism for the stabilization of mast cell tryptase, and these findings can have an important impact on our understanding of how tryptase regulates nuclear events. Full article

(This article belongs to the Special Issue Hematopoietic Serine Proteases: Important Players in Inflammation and Tissue Homeostasis)

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12 pages, 2561 KiB

Open AccessCommunication

Potent and Broad but not Unselective Cleavage of Cytokines and Chemokines by Human Neutrophil Elastase and Proteinase 3

by Zhirong Fu, Srinivas Akula, Michael Thorpe and Lars Hellman

Int. J. Mol. Sci. 2020, 21(2), 651; https://doi.org/10.3390/ijms21020651 - 19 Jan 2020

Cited by 24 | Viewed by 3659

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 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

(This article belongs to the Special Issue Hematopoietic Serine Proteases: Important Players in Inflammation and Tissue Homeostasis)

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13 pages, 4588 KiB

Open AccessArticle

Extended Cleavage Specificities of Two Mast Cell Chymase-Related Proteases and One Granzyme B-Like Protease from the Platypus, a Monotreme

by Zhirong Fu, Srinivas Akula, Michael Thorpe and Lars Hellman

Int. J. Mol. Sci. 2020, 21(1), 319; https://doi.org/10.3390/ijms21010319 - 02 Jan 2020

Cited by 7 | Viewed by 3221

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 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

(This article belongs to the Special Issue Hematopoietic Serine Proteases: Important Players in Inflammation and Tissue Homeostasis)

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17 pages, 6121 KiB

Open AccessArticle

Extended Cleavage Specificities of Rabbit and Guinea Pig Mast Cell Chymases: Two Highly Specific Leu-Ases

by Yuan Zhongwei, Srinivas Akula, Zhirong Fu, Lawrence de Garavilla, Jukka Kervinen, Michael Thorpe and Lars Hellman

Int. J. Mol. Sci. 2019, 20(24), 6340; https://doi.org/10.3390/ijms20246340 - 16 Dec 2019

Cited by 8 | Viewed by 3446

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 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

(This article belongs to the Special Issue Hematopoietic Serine Proteases: Important Players in Inflammation and Tissue Homeostasis)

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Review

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14 pages, 1005 KiB

Open AccessReview

Mast Cell Chymase and Kidney Disease

by Shamila Vibhushan, Manuela Bratti, Juan Eduardo Montero-Hernández, Alaa El Ghoneimi, Marc Benhamou, Nicolas Charles, Eric Daugas and Ulrich Blank

Int. J. Mol. Sci. 2021, 22(1), 302; https://doi.org/10.3390/ijms22010302 - 30 Dec 2020

Cited by 8 | Viewed by 3131

Abstract

A sizable part (~2%) of the human genome encodes for proteases. They are involved in many physiological processes, such as development, reproduction and inflammation, but also play a role in pathology. Mast cells (MC) contain a variety of MC specific proteases, the expression of which may differ between various MC subtypes. Amongst these proteases, chymase represents up to 25% of the total proteins in the MC and is released from cytoplasmic granules upon activation. Once secreted, it cleaves the targets in the local tissue environment, but may also act in lymph nodes infiltrated by MC, or systemically, when reaching the circulation during an inflammatory response. MC have been recognized as important components in the development of kidney disease. Based on this observation, MC chymase has gained interest following the discovery that it contributes to the angiotensin-converting enzyme’s independent generation of angiotensin II, an important inflammatory mediator in the development of kidney disease. Hence, progress regarding its role has been made based on studies using inhibitors but also on mice deficient in MC protease 4 (mMCP-4), the functional murine counterpart of human chymase. In this review, we discuss the role and actions of chymase in kidney disease. While initially believed to contribute to pathogenesis, the accumulated data favor a more subtle view, indicating that chymase may also have beneficial actions. Full article

(This article belongs to the Special Issue Hematopoietic Serine Proteases: Important Players in Inflammation and Tissue Homeostasis)

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