Fibroblast-encoded inflammatory memory orchestrates recurrent skin inflammation via NNMT-dependent metabolic remodeling
Escrito por Yifan Zhou , Kang Li , Yuming Xie , Chencan Su , Zhiguo Li , Yang Yang , Pei Qiao , Wanting Liu , Yaxing Bai , Ke Xue , Johann E. Gudjonsson , Gang Wang y Shuai Shao
Publicado
30 de abril de 2026
Servidor
bioRxiv
Resumen
Chronic skin inflammation frequently recurs at the same anatomical sites after therapy withdrawal, implying stromal cells may encode local inflammatory memory. Here, we identified nicotinamide N-methyltransferase (NNMT) as a central metabolic-epigenetic regulator of fibroblast inflammatory memory enabling psoriasis relapse. Single-cell and spatial transcriptomics revealed that dermal fibroblasts acquire a persistent senescence-associated secretory phenotype (SASP) during inflammation, maintaining pro-inflammatory niche in resolved skin that supports CD 8 + CD 103 + tissue-resident memory T cell (Trm) differentiation. Multi-omics profiling demonstrated that NNMT depletes S-adenosylmethionine (SAM), reduces H 3K 27me3 deposition, and permits sustained AP-1 occupancy at SASP gene promoters. Fibroblast-specific NNMT ablation or pharmacologic inhibition suppressed SASP activity, limited Trm accumulation, and prevented both initiation and relapse of skin inflammation in mice. These findings establish NNMT as a stromal regulator linking fibroblast metabolism to durable epigenetic memory and propose its targeting to erase inflammatory memory and achieve long-term remission in psoriasis and related immune-mediated diseases.
Abstract Figure Graphic Abstract:
Proposed mechanism through which NNMT-driven fibroblast SASP facilitates the initiation and recurrence of psoriasis
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