Aging-associated immune and stromal programs mark interferon- and remodeling-linked spatial contexts in psoriatic...

Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by spatially organized epithelial, stromal, vascular, and immune interactions. Although aging is associated with inflammatory activation and tissue remodeling in skin, it remains unclear how aging-associated transcriptional programs are positioned within psoriatic tissue architecture and whether stromal cells with senescence-associated features retain inflammatory responsiveness.

We integrated a normal aging human skin single-cell RNA-seq dataset with discovery and external psoriasis spatial transcriptomic datasets. Three compartment-informed aging signatures-global old-up, stromal-aging, and immune-aging-were defined and projected onto psoriatic tissue. Sensitivity analyses included an overlap-removed immune-aging score and immune/APC-adjusted analyses. Human foreskin fibroblasts were used as a reductionist system to test whether doxorubicin-induced senescence-like stress was compatible with IFNγ-responsive antigen-presentation-associated and chemokine programs.

Aging-associated signals were not uniformly distributed across psoriatic lesions. Global old-up and immune-aging programs were higher in APC/immune-enriched and immune-inflammatory domains, whereas stromal-aging localized to fibro-inflammatory and extracellular matrix-remodeling domains. Score-defined immune-aging-high regions showed IFN-linked chemokine, inflammatory, and immune-activation features, while stromal-aging-high regions were dominated by collagen organization and extracellular matrix remodeling. At the tissue-section level, immune-aging activity was increased in lesional psoriasis and was associated with IFN gamma response and antigen-presentation activity, with similar patterns observed using the overlap-removed immune-aging score. External spatial transcriptomic analysis reproduced selected antigen-presentation- and interferon-linked features. In HFF-1 fibroblasts, doxorubicin induced a senescence-like DNA damage-associated state, whereas IFNγ induced HLA-ABC, B2M, CD74, CXCL9, and surface HLA-DR. These IFNγ-responsive programs remained detectable after doxorubicin-induced stress.

Aging-associated transcriptional programs are spatially organized within psoriatic skin through distinct immune- and stromal-associated tissue contexts. The findings support the coexistence of senescence-like stromal stress and IFNγ-responsive immune activation but do not establish a causal relationship between these processes.