Granzyme H Is a Novel Protease Expressed by Human Mast Cells

Rönnberg, Elin; Calounova, Gabriela; Sutton, Vivien R.; Trapani, Joseph A.; Rollman, Ola; Hagforsen, Eva; Pejler, Gunnar

doi:10.1159/000368403

Cited by 16 publications

(10 citation statements)

References 30 publications

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“…The classification of mast cells into connective tissue and mucosa, with distinct heparin or chondroitin sulphate contents, is based on rodent examples and may not be generalizable to all species and tissues. More recently, confirmed human mast cell proteases include granzyme H (Rönnberg et al, 2014).…”

Section: G Interactions Between Heparin and Pathogensmentioning

confidence: 91%

Pharmacology of Heparin and Related Drugs

et al. 2015

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Section: G Interactions Between Heparin and Pathogensmentioning

confidence: 91%

Pharmacology of Heparin and Related Drugs

et al. 2015

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“…BMMCs were prepared and cultured as described . Human cord blood‐derived mast cells (CBMCs) were generated as described previously . Eosinophil and neutrophil granulocytes were isolated from peripheral blood from two healthy donors: 80 ml of heparinized blood was obtained from each donor, and granulocytes were isolated by Percoll (1.082 g/ml) gradient centrifugation.…”

Section: Methodsmentioning

confidence: 99%

Ablation of human skin mast cells in situ by lysosomotropic agents

Hagforsen

Paivandy

Lampinen

et al. 2015

Experimental Dermatology

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Mast cells are known to have a detrimental impact on numerous types of inflammatory skin diseases such as contact dermatitis, atopic eczema and cutaneous mastocytosis. Regimens that dampen skin mast cell-mediated activities can thus offer an attractive therapeutic option under such circumstances. As mast cells are known to secrete a large array of potentially pathogenic compounds, both from preformed stores in secretory lysosomes (granules) and after de novo synthesis, mere inhibition of degranulation or interference with individual mast cell mediators may not be sufficient to provide an effective blockade of harmful mast cell activities. An alternative strategy may therefore be to locally reduce skin mast cell numbers. Here, we explored the possibility of using lysosomotropic agents for this purpose, appreciating the fact that mast cell granules contain bioactive compounds prone to trigger apoptosis if released into the cytosolic compartment. Based on this principle, we show that incubation of human skin punch biopsies with the lysosomotropic agents siramesine or Leu-Leu methyl ester preferably ablated the mast cell population, without causing any gross adverse effects on the skin morphology. Subsequent analysis revealed that mast cells treated with lysosomotropic agents predominantly underwent apoptotic rather than necrotic cell death. In summary, this study raises the possibility of using lysosomotropic agents as a novel approach to targeting deleterious mast cell populations in cutaneous mastocytosis and other skin disorders negatively influenced by mast cells.

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“…Mast cells of humans and mice can also express granzymes, the activation of which presumably would be affected by inhibition of CatC (McGuire, Lipsky, & Thiele, 1993;Ronnberg, et al, 2014;Strik, et al, 2007;Wroblewski, et al, 2017) A C C E P T E D M A N U S C R I P T…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Therapeutic targeting of cathepsin C: from pathophysiology to treatment

Korkmaz¹,

Caughey²,

Chapple³

et al. 2018

Pharmacology & Therapeutics

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Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects mediated by these proteases in inflammatory/auto-immune disorders. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome (PLS). The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials.

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Granzyme H Is a Novel Protease Expressed by Human Mast Cells

Cited by 16 publications

References 30 publications

Pharmacology of Heparin and Related Drugs

Pharmacology of Heparin and Related Drugs

Ablation of human skin mast cells in situ by lysosomotropic agents

Therapeutic targeting of cathepsin C: from pathophysiology to treatment

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