Aged human skin accumulates mast cells with altered functionality that localize to macrophages and vasoactive intestinal peptide‐positive nerve fibres

Abstract

Summary Background Skin health declines with age and this is partially attributed to immunosenescence. Mast cells ( MC s) are innate immune cells that coordinate tissue immune responses integral to skin homeostasis and disease. Objectives To understand how MC s contribute to human skin ageing, we investigated how intrinsic ageing impacts MC phenotype and MC relationships with other immune cells and skin structures. Methods In photoprotected skin biopsies from young (≤ 30 years) and aged (≥ 75 years) individuals, immunostaining and spatial morphometry were performed to identify changes in MC phenotype, number, distribution and interaction with the vasculature and nerve fibres. Quantitative polymerase chain reaction was used to measure changes in gene expression related to immune cell activity and neuropeptide signalling. Results Skin MC s, macrophages and CD 8 + T cells increased in number in intrinsically aged vs. young skin by 40%, 44% and 90%, respectively ( P < 0·05), while CD 4 + T cells and neutrophils were unchanged. In aged skin, MC s were more numerous in the papillary dermis and showed a reduced incidence of degranulation (50% lower than in young, P < 0·01), a conserved tryptase–chymase phenotype and coexpression of granzyme B. In aged skin, MC s increased their association with macrophages (~ 48% vs. ~27%, P < 0·05) and nerve fibres (~29% vs. 16%, P < 0·001), while reducing their interactions with blood vessels (~34% vs. 45%, P < 0·001). Additionally, we observed modulation of gene expression of vasoactive intestinal peptide ( VIP ; increased) and substance P (decreased) with age; this was associated with an increased frequency of VIP + nerve fibres (around three times higher in aged skin, P < 0·05), which were strongly associated with MC s (~19% in aged vs. 8% in young, P < 0·05). Conclusions In photoprotected skin we observed an accumulation of MC s with increasing age. These MC s have both altered functionality and distribution within the skin, which supports a role for these cells in altered tissue homeostasis during ageing.

The Dynamics of the Skin’s Immune System

“…In humans, mast cells are found in all areas of the skin but are most numerous in the arms and the legs [176]. The density of mast cells in the papillary dermis increases with age and they are most often localized in the proximity of PGP9.5+ nerve fibers expressing vasoactive intestinal peptide (VIP), which was shown to suppress mast cell degranulation [177]. This has been associated with the reduction of the amount of extracellular matrix remodeling in the skin observed during the later stages of life.…”

Mast Cells in the Skin: Defenders of Integrity or Offenders in Inflammation?

“…MCs have been reported to be very important as regulators of epidermal barrier function and skin homeostasis and play important roles in wound healing and skin aging [ 6 , 22 , 23 , 24 , 25 , 26 , 27 ]. Their role in skin homeostasis has been often reported, but so far, the underlying mechanisms could not be identified in detail.…”

Granzyme B mediates impaired healing of pressure injuries in aged skin

“…Mast cell-derived GzmB expression is also observed in intrinsically aged skin from human donors 29 and mice exposed to chronic, low-dose UV irradiation 7 . Saliently, dermal mast cells express and secrete GzmB 7 , 30 , while cytotoxic T-lymphocytes showed no GzmB in intrinsically aged skin 29 . Providing a smaller overall contribution to expression in PI, GzmB also appeared to be expressed by a subset of CD68+ cells.…”