Inducible senescence in cultured mast cells as a model for elucidating the impact of aging on mast cell functions
2Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics School, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel
Resolving age-related changes in immune cells, including mast cells (MCs), is critical for the understanding of age-related diseases. Indeed, apart from their known role in allergy, MC involvement was documented in diseases such as Alzheimer’s disease and Parkinson’s disease. However, deciphering the influence of aging on MC function has been hampered by the difficulty of retrieving tissue MCs from old mice, leaving the need for a model for “old” MCs unmet. To overcome this problem, we relied on the fact that cellular senescence is tightly linked to aging. Taking advantage of the fact that MCs can be generated by in vitro differentiation of progenitor cells from the bone marrow of young mice (BMMCs), we established an in vitro model of inducible senescence in MCs, that is based on MC differentiation from transgenic mice, that carry a tet-on-system of p16. The latter is an inhibitor of the cell cycle, the upregulation of which causes senescence. We have confirmed that BMMCs derived from these mice upregulate p16 in response to doxycycline and stop proliferation. Further characterization revealed an increased expression of mRNA of members of the senescence-associated secretory phenotype, such as IL-1β, in these cells. Importantly, senescence enhances the proinflammatory responses of MCs to both allergic (i.e. IgE/antigen), and innate immune responses, while the cell surface expression of the FcεRI-receptor for IgE was decreased. We also noted differences in mitochondrial respiration and a decrease in autophagy. Collectively, our results imply that senescence/aging induce metabolic changes and reprogram MCs towards a pro-inflammatory phenotype.