The role of fibroblast senescence in cutaneous immune ageing

Senescence is a state of irreversible cell cycle arrest that arises in response to DNA damage and protects cells from neoplastic transformation. As a consequence, senescent cells accumulate in human tissues during ageing and exhibit a unique senescence- associated secretory phenotype or ‘SASP’. This SASP is comprised of immunomodulatory molecules and is the main way senescent cells contribute to age- related pathology such as atherosclerosis, diabetes, sarcopenia and osteoporosis. // Antigen-specific immunity declines with age and increases the risk of cancer, infection and vaccination failure. This decline can be quantified in the skin by measuring the delayed-type hypersensitivity (DTH) response to a recall antigen like varicella zoster virus (VZV)-glycoprotein. The overarching aim of this work, therefore, is to determine whether the accumulation of senescent stromal cells in the skin contributes to a decline in antigen-specific cutaneous immunity. // Early in this study, limitations of existing markers for the detection of senescent cells in human skin were identified and the use of telomere-associated γH2AX foci (TAF) was validated as an alternative marker in frozen sections. Using TAF, senescence in each compartment of the skin was quantified and a strong association was found between the number of TAF+ fibroblasts in the interstitial dermis and poorer DTH responses to intradermal injection of VZV-glycoprotein. Interestingly, it was found that the early inflammation generated by the trauma of intradermal injection resulted in the clearance of senescent cells from the interstitial dermis of old skin. A population of NK-like CD8+ T- cells present in the dermis of old skin were identified and may be responsible for their clearance. Finally, it was demonstrated that systemic treatment with p38MAPK inhibitor losmapimod reduced the SASP gene signature, decreased the expression of activatory NK-R ligand MICA/B and protected senescent interstitial cells from inflammation-induced clearance in old human skin. Together, these findings provide evidence that support the hypothesis that senescent fibroblasts contribute to the decline in antigen-specific immunity in human skin during ageing