Reactive Lipids From the Secretome of Senescent Fibroblasts Modify the Extracellular Matrix With Functional Consequences for Resident Cells

Reactive lipids such as POVPC and PONPC accumulate in senescent dermal fibroblasts and can modify the extracellular matrix (ECM) proteins, particularly collagens I, II, and IV, through covalent binding. This modification affects the function of resident cells, with fibroblasts showing a transient inflammatory phenotype and macrophages exhibiting modification-specific chemokine expression. Additionally, 4-HNE and OxPAPC induce an early senescent phenotype, and TLR signaling is impaired in a modification-dependent manner. When modified collagen was used to create organotypic skin, it resulted in disrupted differentiation of epidermal keratinocytes. These findings suggest that factors derived from senescent cells can modulate inflammation and help these cells evade clearance by phagocytic cells.