A Prominent Pro-Inflammatory Phenotype Is Observed in Replication and Stress-Induced Senescent Mast Cells.

Abstract

Mast cells (MC) are long-lived important immune effectors that control inflammation, allergies, and innate immunity reactions, but the expression of specific markers in replicative and stress-induced senescence in this cell type, together with its relevance in vivo, has not been described. Here, bone marrow-derived MCs (BMMC) were generated from young C57BL6/J mice and kept in culture for a long time or treated with the well-known stressor bacterial lipopolysaccharide (LPS) to promote replicative and stress-induced senescence, respectively. Changes in size, granularity, and expression of p16^INK4A and p21^CIP1/WAF1, together with cell cycle arrest and senescence-associated-β-Galactosidase (SA-β-Gal) activity, were observed after 12 weeks in culture, with minimal changes in cell viability but important modifications in cell metabolism. Senescence-associated secretory phenotype (SASP) included IL-23, IL-6, and VEGF, among other cytokines and chemokines. Maximal FcεRI and TLR4-dependent cell activation was diminished by replicative senescence in BMMC. Stress-induced senescence produced cell cycle arrest, increased β-Gal expression, and transient high cytokine expression. Utilizing aged MC-deficient (c-Kit^Wsh/Wsh) and c-Kit^Wsh/Wsh mice reconstituted with MC, the exacerbated cytokine production observed in senescent cells was confirmed in the rapid, canonical MC-dependent response to acute intraperitoneal LPS administration. Finally, high basal cytokine production was detected in MC purified from chronically LPS-treated animals. Our data show that (1) senescence markers appear in replication and stress-induced senescence of MCs; (2) basal and activated effector functions of MC are altered by senescence; and (3) aging is associated with increased MC-dependent inflammatory responses. Our results show that senescence importantly affects MC function, which could contribute to inflammaging.