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Melo, F. R., Martin, S. S., Sommerhoff, C. P. & Pejler, G. (2019). Exosome-mediated uptake of mast cell tryptase into the nucleus of melanoma cells: a novel axis for regulating tumor cell proliferation and gene expression. Cell Death and Disease, 10, Article ID 659.
Open this publication in new window or tab >>Exosome-mediated uptake of mast cell tryptase into the nucleus of melanoma cells: a novel axis for regulating tumor cell proliferation and gene expression
2019 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 659Article in journal (Refereed) Published
Abstract [en]

It is well established that mast cell accumulation accompanies most malignancies. However, the knowledge of how mast cells functionally impact on tumors is still rudimentary. Here we addressed this issue and show that mast cells have anti-proliferative activity on melanoma cells and that this effect is dependent on tryptase, a tetrameric protease stored in mast cell granules. Mechanistically, tryptase was found to be endocytosed by melanoma cells as cargo of DNA-coated exosomes released from melanoma cells, followed by transport to the nucleus. In the nucleus, tryptase executed clipping of histone 3 and degradation of Lamin B1, accompanied by extensive nuclear remodeling. Moreover, tryptase degraded hnRNP A2/B1, a protein involved in mRNA stabilization and interaction with non-coding RNAs. This was followed by downregulated expression of the oncogene EGR1 and of multiple non-coding RNAs, including oncogenic species. Altogether, these findings establish a new principle for regulation of tumor cell proliferation.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-395846 (URN)10.1038/s41419-019-1879-4 (DOI)000488849400002 ()31506436 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietySwedish Heart Lung FoundationKnut and Alice Wallenberg Foundation
Available from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-10-25Bibliographically approved
Desbiens, L., Lapointe, C., Gendron, L., Gharagozloo, M., Vincent, L., Pejler, G., . . . D'Orleans-Juste, P. (2019). Experimental Autoimmune Encephalomyelitis Potentiates Mouse Mast Cell Protease 4-Dependent Pressor Responses to Centrally or Systemically Administered Big Endothelin-1. Journal of Pharmacology and Experimental Therapeutics, 370(3), 437-446
Open this publication in new window or tab >>Experimental Autoimmune Encephalomyelitis Potentiates Mouse Mast Cell Protease 4-Dependent Pressor Responses to Centrally or Systemically Administered Big Endothelin-1
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2019 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 370, no 3, p. 437-446Article in journal (Refereed) Published
Abstract [en]

Multiple sclerosis is a neurodegenerative disease affecting predominantly female patients between 20 and 45 years of age. We previously reported the significant contribution of mouse mast cell protease 4 (mMCP-4) in the synthesis of endothelin-1 (ET-1) in healthy mice and in a murine model of experimental autoimmune encephalomyelitis (EAE). In the current study, the cardiovascular effects of ET-1 and big endothelin-1 (big-ET-1) administered systemically or intrathecally were assessed in the early preclinical phase of EAE in telemetry instrumented/conscious mice. Chymase-specific enzymatic activity was also measured in the lung, brain, and mast cell extracts in vitro. Finally, the impact of EAE immunization was studied on the pulmonary and brain mRNA expression of different genes of the endothelin pathway, interleukin-33 (IL-33), and monitoring of immunoreactive tumor necrosis factor-α (TNF-α). Systemically or intrathecally administered big-ET-1 triggered increases in blood pressure in conscious mice. One week post-EAE, the pressor responses to big-ET-1 were potentiated in wild-type (WT) mice but not in mMCP-4 knockout (KO) mice. EAE triggered mMCP-4–specific activity in cerebral homogenates and peritoneal mast cells. Enhanced pulmonary, but not cerebral preproendothelin-1 and IL-33 mRNA were found in KO mice and further increased 1 week post-EAE immunization, but not in WT animals. Finally, TNF-α levels were also increased in serum from mMCP-4 KO mice, but not WT, 1 week post-EAE. Our study suggests that mMCP-4 activity is enhanced both centrally and systemically in a mouse model of EAE.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-394969 (URN)10.1124/jpet.118.256016 (DOI)000485873600011 ()31248979 (PubMedID)
Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2019-10-11Bibliographically approved
Karlsson, I., Veevnik, D., Fedulov, A., Yurkshtovich, N., Yurkshtovich, T., Pejler, G. & Lokot, I. (2019). Local delivery of temozolomide via a biologically inert carrier (Temodex) prolongs survival in glioma patients, irrespectively of the methylation status of MGMT. Neoplasma (Bratislava), 66(2), 288-293
Open this publication in new window or tab >>Local delivery of temozolomide via a biologically inert carrier (Temodex) prolongs survival in glioma patients, irrespectively of the methylation status of MGMT
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2019 (English)In: Neoplasma (Bratislava), ISSN 0028-2685, E-ISSN 1338-4317, Vol. 66, no 2, p. 288-293Article in journal (Refereed) Published
Abstract [en]

Glioma is the most common brain malignancy. Standard first-line therapy for glioma includes surgery, radiotherapy and systemic administration of temozolomide. However, temozolomide does not reach the brain in sufficient doses when administered orally and has poor efficiency in more than half of the patients. Strategies to improve the treatment of glial malignancies are therefore needed. We have recently developed a system (Temodex) for local administration of temozolomide by encapsulating the drug in a biologically inert matrix. Here, we assessed the effect of Temodex in combination with standard therapy in a small-scale clinical study. Since the efficacy of temozolomide therapy is known to depend on the methylation status of the O-6-methylguanine-DNA methyltransferase gene (MGMT) promoter, we also analyzed whether the effect of Temodex was influenced by the methylation status of MGMT. Our data show that the combination of standard therapy and Temodex was more efficient than standard therapy alone, promoting the overall patient survival by up to 33 weeks. Moreover, the efficacy of Temodex was not dependent on the methylation status of MGMT. Local Temodex administration in combination with standard therapy thereby emerges as a novel therapeutic option, with applicability that is independent on the methylation status of the MGMT promoter.

Place, publisher, year, edition, pages
AEPRESS SRO, 2019
Keywords
glioma, Temodex, temozolomide, MGTM, methylation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-383209 (URN)10.4149/neo_2018_180613N393 (DOI)000465160800016 ()30569719 (PubMedID)
Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-05-10Bibliographically approved
Paivandy, A., Eriksson, J., Melo, F. R., Sellin, M. E. & Pejler, G. (2019). Lysosomotropic challenge of mast cells causes intra-granular reactive oxygen species production. CELL DEATH DISCOVERY, 5, Article ID 95.
Open this publication in new window or tab >>Lysosomotropic challenge of mast cells causes intra-granular reactive oxygen species production
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2019 (English)In: CELL DEATH DISCOVERY, ISSN 2058-7716, Vol. 5, article id 95Article in journal (Refereed) Published
Abstract [en]

Mast cells contribute to the pathology of allergic and other disorders. Strategies to interfere with harmful mast cell-related activities are therefore warranted. Previously we established a principle for inducing selective apoptosis of mast cells, by the use of lysosomotropic agents that cause secretory granule permeabilization, leading to production of reactive oxygen species (ROS). However, the mechanism of ROS production has not been known. Here we addressed this issue. Live microscopy analysis showed that the secretory granules comprise major subcellular compartments for ROS production in response to mefloquine. As further signs for the primary involvement of secretory granules, both ROS production and cell death was blunted in mast cells lacking serglycin, a secretory granule-restricted proteoglycan. Inhibition of granule acidification caused an essentially complete blockade of granule permeabilization, ROS production and cell death in response to mefloquine. ROS production was also attenuated in the presence of an iron chelator, and after inhibition of either granzyme B or the ERK1/2 MAP kinase signaling pathway. Together, our findings reveal that the mast cell secretory granules constitute major sites for ROS production in mast cells subjected to lysosomotropic challenge. Moreover, this study reveals a central role for granule acidification in ROS generation and the pro-apoptotic response triggered downstream of secretory granule permeabilization.

National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-387281 (URN)10.1038/s41420-019-0177-3 (DOI)000468005600001 ()31123601 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2019-06-24Bibliographically approved
Vangansewinkel, T., Lemmens, S., Geurts, N., Quanten, K., Dooley, D., Pejler, G. & Hendrix, S. (2019). Mouse mast cell protease 4 suppresses scar formation after traumatic spinal cord injury. Scientific Reports, 9, Article ID 3715.
Open this publication in new window or tab >>Mouse mast cell protease 4 suppresses scar formation after traumatic spinal cord injury
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 3715Article in journal (Refereed) Published
Abstract [en]

Spinal cord injury (SCI) triggers the formation of a glial and fibrotic scar, which creates a major barrier for neuroregenerative processes. Previous findings indicate that mast cells (MCs) protect the spinal cord after mechanical damage by suppressing detrimental inflammatory processes via mouse mast cell protease 4 (mMCP4), a MC-specific chymase. In addition to these immunomodulatory properties, mMCP4 also plays an important role in tissue remodeling and extracellular matrix degradation. Therefore, we have investigated the effects of mMCP4 on the scarring response after SCI. We demonstrate that the decrease in locomotor performance in mMCP4(-/-) mice is correlated with excessive scar formation at the lesion. The expression of axon-growth inhibitory chondroitin sulfate proteoglycans was dramatically increased in the perilesional area in mMCP4(-/-) mice compared to wild type mice. Moreover, the fibronectin-, laminin-, and collagen IV-positive scar was significantly enlarged in mMCP4(-/-) mice at the lesion center. A degradation assay revealed that mMCP4 directly cleaves collagen IV in vitro. On the gene expression level, neurocan and GFAP were significantly higher in the mMCP4(-/-) group at day 2 and day 28 after injury respectively. In contrast, the expression of fibronectin and collagen IV was reduced in mMCP4(-/-) mice compared to WT mice at day 7 after SCI. In conclusion, our data show that mMCP4 modulates scar development after SCI by altering the gene and protein expression patterns of key scar factors in vivo. Therefore, we suggest a new mechanism via which endogenous mMCP4 can improve recovery after SCI.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-379894 (URN)10.1038/s41598-019-39551-1 (DOI)000460391500098 ()30842526 (PubMedID)
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-03-25Bibliographically approved
Succar, J., Giatsidis, G., Yu, N., Hassan, K., Khouri, R. J., Gurish, M. F., . . . Orgill, D. P. (2019). Mouse Mast Cell Protease-4 Recruits Leukocytes in the Inflammatory Phase of Surgically Wounded Skin. ADVANCES IN WOUND CARE, 8(10), 469-475
Open this publication in new window or tab >>Mouse Mast Cell Protease-4 Recruits Leukocytes in the Inflammatory Phase of Surgically Wounded Skin
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2019 (English)In: ADVANCES IN WOUND CARE, ISSN 2162-1918, Vol. 8, no 10, p. 469-475Article in journal (Refereed) Published
Abstract [en]

Objective: Mouse mast cell protease-4 (mMCP-4, also known as chymase) has both pro- and anti-inflammatory roles depending on the disease model. However, its effects have not been studied in surgically wounded skin. Given the significant clinical applications of modulating the inflammatory response in wound healing, we examined the role of mMCP-4 and the effect of its inhibitor chymostatin on leukocyte and polymorphonuclear cell (PMN) recruitment in our skin model. Approach: Recruitment was assessed on day-1 postwounding of three groups of mice (n = 10 each): mMCP-4 null mice, wild-type (WT) mice treated with the mMCP-4 inhibitor chymostatin, and WT with no other intervention. Leukocytes were stained with CD-45 cell marker, and PMN cells were stained with chloroacetate esterase. Results: The WT mice had 27 +/- 9 leukocytes per field compared with 11 +/- 6 for the mMCP-4 nulls, a decrease of 60% (p = 0.03), whereas the chymostatin-injected group had a count comparable with the uninjected WT controls at 24 +/- 9. The WT group had a PMN count of 96 +/- 12 cells, compared with just 24 +/- 8 in the mMCP-4 null group, a decrease of 75% (p = 0.001), whereas the chymostatin-treated group had 60 +/- 18 cells, a decrease of 38% compared with the WT group (p = 0.03). Innovation: We showed that the inflammatory process can be influenced by impeding the arrival of PMNs into the surgically injured site using the mMCP-4 inhibitor chymostatin. Conclusion: Chymase contributes to the recruitment of white blood cells in surgically wounded skin.

Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2019
Keywords
wound healing, inflammation, mouse mast cell protease-4, leukocytes recruitment, polymorphonuclear cells, chymase
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-395719 (URN)10.1089/wound.2018.0898 (DOI)000488493300002 ()31456904 (PubMedID)
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
von Beek, C., Waern, I., Eriksson, J., Melo, F. R., Robinson, C., Waller, A. S., . . . Pejler, G. (2019). Streptococcal sagA activates a proinflammatory response in mast cells by a sublytic mechanism. Cellular Microbiology, 21(9), Article ID e13064.
Open this publication in new window or tab >>Streptococcal sagA activates a proinflammatory response in mast cells by a sublytic mechanism
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2019 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 21, no 9, article id e13064Article in journal (Refereed) Published
Abstract [en]

Mast cells are implicated in the innate proinflammatory immune defence against bacterial insult, but the mechanisms through which mast cells respond to bacterial encounter are poorly defined. Here, we addressed this issue and show that mast cells respond vividly to wild type Streptococcus equi by up-regulating a panel of proinflammatory genes and by secreting proinflammatory cytokines. However, this response was completely abrogated when the bacteria lacked expression of sagA, whereas the lack of a range of other potential virulence genes (seeH, seeI, seeL, seeM, hasA, seM, aroB, pyrC, and recA) had no effect on the amplitude of the mast cell responses. The sagA gene encodes streptolysin S, a lytic toxin, and we next showed that the wild type strain but not a sagA-deficient mutant induced lysis of mast cells. To investigate whether host cell membrane perturbation per se could play a role in the activation of the proinflammatory response, we evaluated the effects of detergent- and pneumolysin-dependent lysis on mast cells. Indeed, exposure of mast cells to sublytic concentrations of all these agents resulted in cytokine responses of similar amplitudes as those caused by wild type streptococci. This suggests that sublytic membrane perturbation is sufficient to trigger full-blown proinflammatory signalling in mast cells. Subsequent analysis showed that the p38 and Erk1/2 signalling pathways had central roles in the proinflammatory response of mast cells challenged by either sagA-expressing streptococci or detergent. Altogether, these findings suggest that sagA-dependent mast cell membrane perturbation is a mechanism capable of activating the innate immune response upon bacterial challenge.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
mast cells, streptococci, toxins
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-396146 (URN)10.1111/cmi.13064 (DOI)000474727500001 ()31155820 (PubMedID)
Funder
Swedish Foundation for Strategic Research , ICA16-0031Swedish Research Council
Available from: 2019-11-04 Created: 2019-11-04 Last updated: 2019-11-04Bibliographically approved
Gendrin, C., Shubin, N. J., Boldenow, E., Merillat, S., Clauson, M., Power, D., . . . Piliponsky, A. M. (2018). Mast cell chymase decreases the severity of group B Streptococcus infections. Journal of Allergy and Clinical Immunology, 142(1), 120-129
Open this publication in new window or tab >>Mast cell chymase decreases the severity of group B Streptococcus infections
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2018 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 142, no 1, p. 120-129Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Group B Streptococcus (GBS) or Streptococcus agalactiae are β-hemolytic gram-positive bacteria that colonize the lower genital tracts of women and are frequently associated with infections during pregnancy. Innate immune defenses are critical for controlling GBS dissemination and systemic infection. Mast cells are resident sentinel cells that come into contact with pathogens early during colonization and infection.

OBJECTIVE: We aimed to investigate the contribution of chymase to systemic GBS infection and rates of preterm birth.

METHODS: Pharmacologic and genetic approaches using mice deficient in mast cell protease (MCPT) 4, the mouse functional homologue of human chymase, were used.

RESULTS: Our studies show that mast cells release a protease with chymotrypsin-like cleavage specificity in response to GBS. Additionally, increased GBS systemic infection and preterm births were observed in MCPT4-deficient mice versus MCPT4-sufficient mice. Furthermore, we observed that proteolytic cleavage of the host extracellular matrix protein fibronectin by peritoneal cell-derived mast cell lysates diminished GBS adherence. Consistent with this observation, the increase in GBS dissemination and preterm births observed in MCPT4-deficient mice was abolished when GBS was deficient in expression of the fibronectin-binding protein SfbA.

CONCLUSIONS: Taken together, our results suggest that the protective effect of MCPT4 against GBS dissemination and preterm labor can be attributed in part to MCPT4-mediated proteolysis of fibronectin. Our studies reveal a novel role of mast cells in defense against bacterial infections.

Keywords
Group B Streptococcus, chymase, fibronectin, mast cells, mouse mast cell protease 4, proteases
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-340993 (URN)10.1016/j.jaci.2017.07.042 (DOI)000437837500016 ()28916188 (PubMedID)
Funder
NIH (National Institute of Health), T32 HD007233
Available from: 2018-02-05 Created: 2018-02-05 Last updated: 2018-09-21Bibliographically approved
Nyekel, F. N., Pacreau, E., Benadda, S., Msallam, R., Abrink, M., Pejler, G., . . . Gautier, G. (2018). Mast Cell Degranulation Exacerbates Skin Rejection by Enhancing Neutrophil Recruitment. Frontiers in Immunology, 9, Article ID 2690.
Open this publication in new window or tab >>Mast Cell Degranulation Exacerbates Skin Rejection by Enhancing Neutrophil Recruitment
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 2690Article in journal (Refereed) Published
Abstract [en]

Recent evidences indicate an important role of tissue inflammatory responses by innate immune cells in allograft acceptance and survival. Here we investigated the role of mast cells (MC) in an acute male to female skin allograft rejection model using red MC and basophil (RMB) mice enabling conditional MC depletion. Kinetic analysis showed that MCs markedly accelerate skin rejection. They induced an early inflammatory response through degranulation and boosted local synthesis of KC, MIP-2, and TNF. This enhanced early neutrophil infiltration compared to a female-female graft-associated repair response. The uncontrolled neutrophil influx accelerated rejection as antibody-mediated depletion of neutrophils delayed skin rejection. Administration of cromolyn, a MC stabilizer and to a lesser extent ketotifen, a histamine type I receptor antagonist, and absence of MCPT4 chymase also delayed graft rejection. Together our data indicate that mediators contained in secretory granules of MC promote an inflammatory response with enhanced neutrophil infiltration that accelerate graft rejection.

Keywords
mast cells, neutrophils, degranulation, skin, transplantation
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-371051 (URN)10.3389/fimmu.2018.02690 (DOI)000450691100001 ()
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-01-07Bibliographically approved
Frisk, J. M., Kjellén, L., Melo, F. R., Öhrvik, H. & Pejler, G. (2018). Mitogen-Activated Protein Kinase Signaling Regulates Proteoglycan Composition of Mast Cell Secretory Granules. Frontiers in Immunology, 9, Article ID 1670.
Open this publication in new window or tab >>Mitogen-Activated Protein Kinase Signaling Regulates Proteoglycan Composition of Mast Cell Secretory Granules
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 1670Article in journal (Refereed) Published
Abstract [en]

Mast cells (MCs) are characterized by an abundance of lysosome-like secretory granules filled with immunomodulatory compounds including histamine, cytokines, lysosomal hydrolases, MC-restricted proteases, and serglycin proteoglycans. The latter are essential for promoting the storage of other granule compounds and are built up of the serglycin core protein to which highly sulfated and thereby negatively charged glycosaminoglycan (GAG) side chains of heparin or chondroitin sulfate type are attached. In the search for mechanisms operating in regulating MC granule homeostasis, we here investigated the role of mitogen-activated protein kinase (MAPK) signaling. We show that inhibition of MEK1/2 (a MAPK kinase) leads to increased metachromatic staining of MC granules, indicative of increased proteoglycan content. Indeed, MEK1/2 inhibition caused a profound increase in the expression of the gene coding for the serglycin core protein and of genes coding for various enzymes involved in the biosynthesis/sulfation of the GAGs attached to the serglycin core protein. This was accompanied by corresponding increases in the levels of the respective GAGs. Deletion of the serglycin core protein abrogated the induction of enzymes operative in proteoglycan synthesis, indicating that availability of the serglycin proteoglycan core protein has a regulatory function impacting on the expression of the various serglycin-modifying enzymes. MEK1/2 inhibition also caused a substantial increase in the expression of granule-localized, proteoglycan-binding proteases. Altogether, this study identifies a novel role for MAPK signaling in regulating the content of secretory granules in MCs.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
mast cells, mitogen-activated protein kinase, MEK1/2, proteoglycans, heparin, chondroitin sulfate, tryptase, serglycin
National Category
Immunology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-361689 (URN)10.3389/fimmu.2018.01670 (DOI)000439155000001 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Heart Lung FoundationSwedish Cancer Society
Available from: 2018-10-03 Created: 2018-10-03 Last updated: 2018-10-03Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6779-391x

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