The Impact of Tryptase and Epigenetic Mechanisms on Mast Cells

Abstract: Mast cells have a large influence on multiple immune-mediated responses, including allergic conditions, and they have been implicated in various diseases such as arthritis and cancer. Mastocytosis is characterized by abnormal mast cell proliferation induced by mutations in KIT, the stem cell factor (SCF) receptor. Mast cell leukemia is the most aggressive form of systemic mastocytosis, with no curative treatment options. Therefore, a therapy or study that help finding a cure for this disease is urgently needed.In paper I, we studied the effect of histone modification inhibition on mast cells. Our findings showed for the first time that mast cell leukemia cells are highly sensitive to histone methyltransferase inhibition. In paper II, we further investigated mast cell function, examining whether DNA can substitute heparin in stabilizing tryptase enzymatic activity. The mechanism by which tryptase retains its enzymatic activity in the nuclear environment is unknown. Our study demonstrated that double-stranded DNA maintained the enzymatic activity of human β-tryptase and identified that tryptase is located within the nucleus of primary human skin mast cells. The interaction of tryptase with DNA is further investigated in paper III, with the aim of determining whether tryptase can affect the formation of neutrophil extracellular traps (NETs). This study showed for the first time that tryptase of mast cells binds to DNA and it has a significant potentiating effect on the formation of NETs in reaction to neutrophil triggering stimuli. Furthermore, the study showed that DNA-stabilized tryptase has a high capacity for proteolytic modification of a variety of cytokines, implying a regulatory role for NET-bound tryptase in inflammatory processes. Finally, in paper IV, we examined the effect of mast cell apoptosis on histone processing, and the extent to which these processes are reliant on tryptase. The findings demonstrated that using a granule-mediated approach to induce mast cell death resulted in substantial processing of core histones. Additionally, they showed that tryptase is highly required for the processing and that tryptase regulates the amplitude of epigenetic core histone modifications during the process of cell death.Taken together, the findings provide a basis for investigating histone modification inhibition as a potential therapeutic strategy for the disease. Furthermore, they reveal a previously unknown way of mediating mast cell tryptase stabilization and indicate that tryptase plays a role in the regulation of mast cell death, having the potential to influence our experience and understanding of how tryptase affects nuclear processes.