499 Senescent fibroblasts accumulate lysophospholipids with immunomodulatory properties

Abstract

With age, senescent cells accumulate in various tissues, which are causatively linked to a state of chronic inflammation and age-related functional decline. The senescence associated secretory phenotype (SASP), a cocktail of inflammatory cyto/chemokines and matrix proteases, majorly contributes to this phenomena. However, the knowledge on lipid mediators which we recently discovered as members of the SASP is very limited. We investigated whether the composition and amount of bioactive lipid mediators are altered in senescent fibroblasts. Using tandem mass spectrometry, we identified two lysophosphatidylcholines (1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine and 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine; lyso-PCs) to be significantly elevated intracellularly in replicative-, and stress induced premature- senescence of human dermal fibroblasts and we were able to detect the same lipid species in cell supernatants. Telomerase transduced fibroblasts did not display elevated lyso-PCs even at more than seventy population doublings. When we exposed FB to lyso-PC, we found elevated expression and secretion of the chemokines CXCL1 and IL8. In monocyte lineage cells, however, lyso-PCs disturbed TLR2/6-CD36 signaling by the agonist FSL1 and uptake of labeled dextrane and therefore may interfere with the recognition of senescent cells. Thus, we propose that lyso-PCs contribute to the chronic pro-inflammatory environment not only directly, but also indirectly, by disturbing the clearance of senescent cells.