Mast cells (MCs) are immune cells, which are best known for their role in allergy. However, these sentinel cells, which respond to a variety of different triggers and thus are likewise important for adaptive and innate immunity, are involved in the pathology of various diseases many of which are age-related, such as Alzheimer’s disease, Parkinson’s disease or cancer.

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Although it is known that MC number and location in the tissue changes with age, the molecular alterations caused by ageing and their impact on disease progression have not been investigated yet, due to the difficulties of retrieving primary MCs from old tissue.

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To overcome this problem and leaning on the established association of senescence with ageing, we established, validated and characterised a model of inducible senescence in bone marrow derived MCs, that is based on the doxycycline-induced expression of the cell cycle inhibitor p16 (Tet-On), whose expression is increased with age both in mouse peritoneal MCs and in human skin MCs.

 

We could show that senescence impacts MC morphology and function, including the release of the proinflammatory mediators that are pre-stored in secretory granules and released by exocytosis and the expression of proinflammatory cytokines under basal conditions and in response to an innate (e. coli lipopolysaccharide LPS) or adaptive (Immunoglobulin E / Antigen) trigger. In particular, a gradual inhibition of β-hexosaminidase release was noted, as opposed to increased proteoglycan exteriorisation and release of exosomes by senescent MCs. The latter correlated with the senescence induced increase in secretory granules that contain intraluminal vesicles.

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Collectively, our findings suggest that senescence/ageing increases the proinflammatory influence of on their microenvironment. Further, our model provides the opportunities to investigate and assess the changes that occur in MCs with ageing at a molecular level, thus paving the road for the discovery of new drug targets and drug development.