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Article ; Online: Fungal polysaccharides from Inonotus obliquus are agonists for Toll-like receptors and induce macrophage anti-cancer activity.

Wold, Christian Winther / Christopoulos, Panagiotis F / Arias, Maykel A / Dzovor, Deborah Elikplim / Øynebråten, Inger / Corthay, Alexandre / Inngjerdingen, Kari Tvete

Communications biology

2024 Volume 7, Issue 1, Page(s) 222

Abstract: Fungal polysaccharides can exert immunomodulating activity by triggering pattern recognition receptors (PRRs) on innate immune cells such as macrophages. Here, we evaluate six polysaccharides isolated from the medicinal fungus Inonotus obliquus for their ...

Abstract	Fungal polysaccharides can exert immunomodulating activity by triggering pattern recognition receptors (PRRs) on innate immune cells such as macrophages. Here, we evaluate six polysaccharides isolated from the medicinal fungus Inonotus obliquus for their ability to activate mouse and human macrophages. We identify two water-soluble polysaccharides, AcF1 and AcF3, being able to trigger several critical antitumor functions of macrophages. AcF1 and AcF3 activate macrophages to secrete nitric oxide and the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Combined with interferon-γ, the fungal polysaccharides trigger high production of IL-12p70, a central cytokine for antitumor immunity, and induce macrophage-mediated inhibition of cancer cell growth in vitro and in vivo. AcF1 and AcF3 are strong agonists of the PRRs Toll-like receptor 2 (TLR2) and TLR4, and weak agonists of Dectin-1. In comparison, two prototypical particulate β-glucans, one isolated from I. obliquus and one from Saccharomyces cerevisiae (zymosan), are agonists for Dectin-1 but not TLR2 or TLR4, and are unable to trigger anti-cancer functions of macrophages. We conclude that the water-soluble polysaccharides AcF1 and AcF3 from I. obliquus have a strong potential for cancer immunotherapy by triggering multiple PRRs and by inducing potent anti-cancer activity of macrophages.
MeSH term(s)	Mice ; Humans ; Animals ; Fungal Polysaccharides/pharmacology ; Toll-Like Receptor 4 ; Lectins, C-Type ; Toll-Like Receptors ; Macrophages ; Cytokines ; Water ; Inonotus
Chemical Substances	Fungal Polysaccharides ; Toll-Like Receptor 4 ; Lectins, C-Type ; Toll-Like Receptors ; Cytokines ; Water (059QF0KO0R)
Language	English
Publishing date	2024-02-23
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-05853-y
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Article ; Online: Selective Detection of Active Extracellular Granzyme A by Using a Novel Fluorescent Immunoprobe with Application to Inflammatory Diseases.

Senan-Salinas, Ana / Comas, Laura / Esteban, Patricia / Garzón-Tituaña, Marcela / Cheng, Zhiming / Santiago, Llipsy / Domingo, Maria Pilar / Ramírez-Labrada, Ariel / Paño-Pardo, José Ramón / Vendrell, Marc / Pardo, Julián / Arias, Maykel A / Galvez, Eva M

ACS pharmacology & translational science

2024 Volume 7, Issue 5, Page(s) 1474–1484

Abstract: Granzymes (Gzms), a family of serine proteases, expressed by immune and nonimmune cells, present perforin-dependent and independent intracellular and extracellular functions. When released in the extracellular space, GzmA, with trypsin-like activity, is ... ...

Abstract	Granzymes (Gzms), a family of serine proteases, expressed by immune and nonimmune cells, present perforin-dependent and independent intracellular and extracellular functions. When released in the extracellular space, GzmA, with trypsin-like activity, is involved in the pathophysiology of different inflammatory diseases. However, there are no validated specific systems to detect active forms of extracellular GzmA, making it difficult to assess its biological relevance and potential use as a biomarker. Here, we have developed fluorescence-energy resonance-transfer (FRET)-based peptide probes (FAM-peptide-DABCYL) to specifically detect GzmA activity in tissue samples and biological fluids in both mouse and human samples during inflammatory diseases. An initial probe was developed and incubated with GzmA and different proteases like GzmB and others with similar cleavage specificity as GzmA like GzmK, thrombin, trypsin, kallikrein, or plasmin. After measuring fluorescence, the probe showed very good specificity and sensitivity for human and mouse GzmA when compared to GzmB, its closest homologue GzmK, and with thrombin. The specificity of this probe was further refined by incubating the samples in a coated plate with a GzmA-specific antibody before adding the probe. The results show a high specific detection of soluble GzmA even when compared with other soluble proteases with very similar cleavage specificity like thrombin, GzmK, trypsin, kallikrein, or plasmin, which shows nearly no fluorescence signal. The high specific detection of GzmA was validated, showing that using pure proteins and serum and tissue samples from GzmA-deficient mice presented a significant reduction in the signal compared with WT mice. The utility of this system in humans was confirmed, showing that GzmA activity was significantly higher in serum samples from septic patients in comparison with healthy donors. Our results present a new immunoprobe with utility to detect extracellular GzmA activity in different biological fluids, confirming the presence of active forms of the soluble protease in vivo during inflammatory and infectious diseases.
Language	English
Publishing date	2024-04-22
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.4c00065
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Article ; Online: Recalling the Biological Significance of Immune Checkpoints on NK Cells: A Chance to Overcome LAG3, PD1, and CTLA4 Inhibitory Pathways by Adoptive NK Cell Transfer?

Lanuza, Pilar M / Pesini, Cecilia / Arias, Maykel A / Calvo, Carlota / Ramirez-Labrada, Ariel / Pardo, Julian

Frontiers in immunology

2020 Volume 10, Page(s) 3010

Abstract: Immune checkpoint receptors (IC) positively or negatively regulate the activation of the host immune response, preventing unwanted reactions against self-healthy tissues. In recent years the term IC has been mainly used for the inhibitory ICs, which are ... ...

Abstract	Immune checkpoint receptors (IC) positively or negatively regulate the activation of the host immune response, preventing unwanted reactions against self-healthy tissues. In recent years the term IC has been mainly used for the inhibitory ICs, which are critical to control Natural Killer (NK) and Cytotoxic CD8
MeSH term(s)	Adoptive Transfer/methods ; Animals ; Antigens, CD/immunology ; CD8-Positive T-Lymphocytes/immunology ; CTLA-4 Antigen/immunology ; Humans ; Killer Cells, Natural/immunology ; Programmed Cell Death 1 Receptor/immunology ; Tumor Microenvironment/immunology
Chemical Substances	Antigens, CD ; CTLA-4 Antigen ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2020-01-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.03010
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Article: Fluorogenic Granzyme A Substrates Enable Real-Time Imaging of Adaptive Immune Cell Activity.

Cheng, Zhiming / Thompson, Emily J / Mendive-Tapia, Lorena / Scott, Jamie I / Benson, Sam / Kitamura, Takanori / Senan-Salinas, Ana / Samarakoon, Youhani / Roberts, Edward W / Arias, Maykel A / Pardo, Julian / Galvez, Eva M / Vendrell, Marc

Angewandte Chemie (Weinheim an der Bergstrasse, Germany)

2023 Volume 135, Issue 8, Page(s) e202216142

Abstract: Cytotoxic immune cells, including T lymphocytes (CTLs) and natural killer (NK) cells, are essential components of the host response against tumors. CTLs and NK cells secrete granzyme A (GzmA) upon recognition of cancer cells; however, there are very few ... ...

Abstract	Cytotoxic immune cells, including T lymphocytes (CTLs) and natural killer (NK) cells, are essential components of the host response against tumors. CTLs and NK cells secrete granzyme A (GzmA) upon recognition of cancer cells; however, there are very few tools that can detect physiological levels of active GzmA with high spatiotemporal resolution. Herein, we report the rational design of the near-infrared fluorogenic substrates for human GzmA and mouse GzmA. These activity-based probes display very high catalytic efficiency and selectivity over other granzymes, as shown in tissue lysates from wild-type and GzmA knock-out mice. Furthermore, we demonstrate that the probes can image how adaptive immune cells respond to antigen-driven recognition of cancer cells in real time.
Language	English
Publishing date	2023-01-16
Publishing country	Germany
Document type	Journal Article
ZDB-ID	506609-8
ISSN	1521-3757 ; 0044-8249 ; 0932-2140
ISSN (online)	1521-3757
ISSN	0044-8249 ; 0932-2140
DOI	10.1002/ange.202216142
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Article ; Online: Fluorogenic Granzyme A Substrates Enable Real-Time Imaging of Adaptive Immune Cell Activity.

Angewandte Chemie (International ed. in English)

2023 Volume 62, Issue 8, Page(s) e202216142

Abstract	Cytotoxic immune cells, including T lymphocytes (CTLs) and natural killer (NK) cells, are essential components of the host response against tumors. CTLs and NK cells secrete granzyme A (GzmA) upon recognition of cancer cells; however, there are very few tools that can detect physiological levels of active GzmA with high spatiotemporal resolution. Herein, we report the rational design of the near-infrared fluorogenic substrates for human GzmA and mouse GzmA. These activity-based probes display very high catalytic efficiency and selectivity over other granzymes, as shown in tissue lysates from wild-type and GzmA knock-out mice. Furthermore, we demonstrate that the probes can image how adaptive immune cells respond to antigen-driven recognition of cancer cells in real time.
MeSH term(s)	Animals ; Humans ; Mice ; Fluorescent Dyes ; Granzymes ; Killer Cells, Natural ; Mice, Knockout ; T-Lymphocytes, Cytotoxic
Chemical Substances	Fluorescent Dyes ; Granzymes (EC 3.4.21.-) ; GZMA protein, human (EC 3.4.21.78)
Language	English
Publishing date	2023-01-16
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202216142
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Article ; Online: All About (NK Cell-Mediated) Death in Two Acts and an Unexpected Encore: Initiation, Execution and Activation of Adaptive Immunity.

Ramírez-Labrada, Ariel / Pesini, Cecilia / Santiago, Llipsy / Hidalgo, Sandra / Calvo-Pérez, Adanays / Oñate, Carmen / Andrés-Tovar, Alejandro / Garzón-Tituaña, Marcela / Uranga-Murillo, Iratxe / Arias, Maykel A / Galvez, Eva M / Pardo, Julián

Frontiers in immunology

2022 Volume 13, Page(s) 896228

Abstract: NK cells are key mediators of immune cell-mediated cytotoxicity toward infected and transformed cells, being one of the main executors of cell death in the immune system. NK cells recognize target cells through an array of inhibitory and activating ... ...

Abstract	NK cells are key mediators of immune cell-mediated cytotoxicity toward infected and transformed cells, being one of the main executors of cell death in the immune system. NK cells recognize target cells through an array of inhibitory and activating receptors for endogenous or exogenous pathogen-derived ligands, which together with adhesion molecules form a structure known as immunological synapse that regulates NK cell effector functions. The main and best characterized mechanisms involved in NK cell-mediated cytotoxicity are the granule exocytosis pathway (perforin/granzymes) and the expression of death ligands. These pathways are recognized as activators of different cell death programmes on the target cells leading to their destruction. However, most studies analyzing these pathways have used pure recombinant or native proteins instead of intact NK cells and, thus, extrapolation of the results to NK cell-mediated cell death might be difficult. Specially, since the activation of granule exocytosis and/or death ligands during NK cell-mediated elimination of target cells might be influenced by the stimulus received from target cells and other microenvironment components, which might affect the cell death pathways activated on target cells. Here we will review and discuss the available experimental evidence on how NK cells kill target cells, with a special focus on the different cell death modalities that have been found to be activated during NK cell-mediated cytotoxicity; including apoptosis and more inflammatory pathways like necroptosis and pyroptosis. In light of this new evidence, we will develop the new concept of cell death induced by NK cells as a new regulatory mechanism linking innate immune response with the activation of tumour adaptive T cell responses, which might be the initiating stimulus that trigger the cancer-immunity cycle. The use of the different cell death pathways and the modulation of the tumour cell molecular machinery regulating them might affect not only tumour cell elimination by NK cells but, in addition, the generation of T cell responses against the tumour that would contribute to efficient tumour elimination and generate cancer immune memory preventing potential recurrences.
MeSH term(s)	Adaptive Immunity ; Cytotoxicity, Immunologic ; Humans ; Killer Cells, Natural ; Ligands ; Neoplasms ; Tumor Microenvironment
Chemical Substances	Ligands
Language	English
Publishing date	2022-05-16
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.896228
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Article ; Online: PD-1 is expressed in cytotoxic granules of NK cells and rapidly mobilized to the cell membrane following recognition of tumor cells.

Pesini, Cecilia / Hidalgo, Sandra / Arias, Maykel A / Santiago, Llipsy / Calvo, Carlota / Ocariz-Díez, Maitane / Isla, Dolores / Lanuza, Pilar M / Agustín, M José / Galvez, Eva M / Ramírez-Labrada, Ariel / Pardo, Julián

Oncoimmunology

2022 Volume 11, Issue 1, Page(s) 2096359

Abstract: The contribution of the T cell-related inhibitory checkpoint PD-1 to the regulation of NK cell activity is still not clear with contradictory results concerning its expression and role in the modulation of NK cell cytotoxicity. We provide novel key ... ...

Abstract	The contribution of the T cell-related inhibitory checkpoint PD-1 to the regulation of NK cell activity is still not clear with contradictory results concerning its expression and role in the modulation of NK cell cytotoxicity. We provide novel key findings on the mechanism involved in the regulation of PD-1 expression on NK cell membrane and its functional consequences for the elimination of cancer cells. In contrast to freshly isolated NK cells from cancer patients, those from healthy donors did not express PD-1 on the cell membrane. However, when healthy NK cells were incubated with tumor target cells, membrane PD-1 expression increased, concurrent with the CD107a surface mobilization. This finding suggested that PD-1 was translocated to the cell membrane during NK cell degranulation after contact with target cells. Indeed, cytosolic PD-1 was expressed in freshly-isolated-NK cells and partly co-localized with CD107a and GzmB, confirming that membrane PD-1 corresponded to a pool of preformed PD-1. Moreover, NK cells that had mobilized PD-1 to the cell membrane presented a significantly reduced anti-tumor activity on PD-L1-expressing-tumor cells
MeSH term(s)	Antineoplastic Agents ; Cell Membrane/metabolism ; Humans ; Immunotherapy ; Killer Cells, Natural/metabolism ; Lymphocyte Activation ; Neoplasms
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2022-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2022.2096359
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Article ; Online: Cell death induced by cytotoxic CD8

Jaime-Sanchez, Paula / Uranga-Murillo, Iratxe / Aguilo, Nacho / Khouili, Sofia C / Arias, Maykel A / Sancho, David / Pardo, Julian

Journal for immunotherapy of cancer

2020 Volume 8, Issue 1

Abstract: Background: Elimination of cancer cells by some stimuli like chemotherapy and radiotherapy activates anticancer immunity after the generation of damage-associated molecular patterns, a process recently named immunogenic cell death (ICD). Despite the ... ...

Abstract	Background: Elimination of cancer cells by some stimuli like chemotherapy and radiotherapy activates anticancer immunity after the generation of damage-associated molecular patterns, a process recently named immunogenic cell death (ICD). Despite the recent advances in cancer immunotherapy, very little is known about the immunological consequences of cell death activated by cytotoxic CD8 Methods: ICD induced by Tc cells on EL4 cells was analyzed in tumor by vaccinating mice with EL4 cells killed Results: Mice immunized with EL4.gp33 cells killed in vitro or in vivo by gp33-specific Tc cells were protected from parental EL4 tumor development. This result was confirmed in vivo by using ovalbumin (OVA) as another surrogate antigen. Perforin and TLR4 and BATF3-dependent type 1 conventional dendritic cells (cDC1s) were required for protection against tumor development, indicating cross-priming of Tc cells against endogenous EL4 tumor antigens. Tc cells induced ICD signals in EL4 cells. Notably, ICD of EL4 cells was dependent on caspase-3 activity, with reduced antitumor immunity generated by caspase-3-deficient EL4 cells. In contrast, overexpression of Bcl-X Conclusions: Elimination of tumor cells by Ag-specific Tc cells is immunogenic and protects against tumor development by generating new Tc cells against EL4 endogenous antigens. This finding helps to explain the enhanced efficacy of T cell-dependent immunotherapy and provide a molecular basis to explain the epitope spread phenomenon observed during vaccination and chimeric antigen receptor (CAR)-T cell therapy. In addition, they suggest that caspase-3 activity in the tumor may be used as a biomarker to predict cancer recurrence during T cell-dependent immunotherapies.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Caspase 3/metabolism ; Cell Death ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Lymphoma, T-Cell/immunology ; Lymphoma, T-Cell/metabolism ; Lymphoma, T-Cell/pathology ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Cytotoxic/metabolism
Chemical Substances	Antigens, Neoplasm ; Caspase 3 (EC 3.4.22.-)
Language	English
Publishing date	2020-04-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2020-000528
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Article ; Online: NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells.

Layunta, Elena / Latorre, Eva / Forcén, Raquel / Grasa, Laura / Castro, Marta / Arias, Maykel A / Alcalde, Ana I / Mesonero, José Emilio

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2018 Volume 47, Issue 3, Page(s) 1217–1229

Abstract: Background/aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate ... ...

Abstract	Background/aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in inflammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Methods: Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice deficient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. Results: NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression significantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. Conclusions: It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression.
MeSH term(s)	Animals ; Caco-2 Cells ; Enterocytes/cytology ; Enterocytes/metabolism ; Humans ; Intestinal Mucosa/cytology ; Intestinal Mucosa/metabolism ; Mice ; Mice, Knockout ; Nod2 Signaling Adaptor Protein/genetics ; Nod2 Signaling Adaptor Protein/metabolism ; Serotonin Plasma Membrane Transport Proteins/genetics ; Serotonin Plasma Membrane Transport Proteins/metabolism ; Toll-Like Receptor 2/genetics ; Toll-Like Receptor 2/metabolism ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 4/metabolism
Chemical Substances	Card15 protein, mouse ; Nod2 Signaling Adaptor Protein ; Serotonin Plasma Membrane Transport Proteins ; Slc6a4 protein, mouse ; Tlr2 protein, mouse ; Tlr4 protein, mouse ; Toll-Like Receptor 2 ; Toll-Like Receptor 4
Language	English
Publishing date	2018-06-15
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.1159/000490218
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Article ; Online: The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover.

Garzón-Tituaña, Marcela / Arias, Maykel A / Sierra-Monzón, José L / Morte-Romea, Elena / Santiago, Llipsy / Ramirez-Labrada, Ariel / Martinez-Lostao, Luis / Paño-Pardo, José R / Galvez, Eva M / Pardo, Julián

Frontiers in immunology

2020 Volume 11, Page(s) 1054

Abstract: Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is ...

Abstract	Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem.
MeSH term(s)	Animals ; Blood Coagulation ; Blood Platelets/physiology ; Capillary Permeability ; Cytokine Release Syndrome/enzymology ; Cytokine Release Syndrome/etiology ; Cytokine Release Syndrome/immunology ; Cytokines/metabolism ; Disease Models, Animal ; Granzymes/immunology ; Granzymes/metabolism ; Humans ; Immune Tolerance ; Inflammation Mediators/immunology ; Inflammation Mediators/metabolism ; Models, Biological ; Receptors, Proteinase-Activated/metabolism ; Sepsis/enzymology ; Sepsis/immunology ; Sepsis/physiopathology
Chemical Substances	Cytokines ; Inflammation Mediators ; Receptors, Proteinase-Activated ; Granzymes (EC 3.4.21.-)
Language	English
Publishing date	2020-06-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01054
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