Decoding the mechanism of inflammatory memory in human epithelia

The National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded New York University $148,062 on September 30, 2025, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846).

The funded research investigates the mechanism by which epithelial stem and progenitor cells encode inflammatory memory in psoriasis and other remitting-relapsing inflammatory disorders. The study tests whether homeostatic and inflammatory transcription factors dynamically control epithelial memory formation following inflammation. The research will employ human keratinocyte culture systems and expression modulation techniques to examine how transcription factor levels influence the encoding and retention of cellular inflammatory memory in human epithelial cells.

Performance occurs at New York University School of Medicine in New York, New York, with a period of performance from award date through May 31, 2028.

Abstract

Remitting-relapsing inflammatory disorders affect millions of people and have no cure. Psoriasis (PSO) is a prototypic remitting-relapsing inflammatory disease that despite treatment success in promoting symptom remission, patient relapse almost always occurs. Psoriatic lesions often recur in the same location, indicative of locally encoded disease memory. Our lab and others have uncovered that epithelial stem and progenitor cells (espcs) can remember inflammation by epigenetic mechanisms in murine models of disease. These long-lived cells maintain chromatin accessibility to stress response genes long after inflammatory resolution. My preliminary data suggest that keratinocyte stem cells in skin from resolved psoriatic lesions have an enrichment of inflammatory transcription factors' binding motifs in their differentially accessible regions. Additionally, my preliminary data indicate that keratinocytes capable of encoding inflammatory memory and becoming sensitized to secondary challenge have decreased binding activity of homeostatic transcription factors. The possibly contrasting roles of inflammatory and homeostatic transcription factors in encoding inflammatory memory of human epithelial cells is not understood. In this proposal, i will test the hypothesis that levels of homeostatic VS. Inflammatory TFS dynamically control epithelial memory formation following inflammation. My proposed studies will utilize a human keratinocyte culture system and cutting-edge expression system to modulate levels of homeostatic and inflammatory transcription factors and test their role in encoding and retaining cellular memory. Altogether, these studies will decode the mechanistic effect that transcription factors have on inflammatory memory encoding in human epithelial cells, potentially uncovering a critical disease mechanism in remitting relapsing inflammatory disorders. Understanding the cellular and molecular basis of PSO disease memory in espcs, as i propose here, could pave the way for developing curative therapies that limit relapse.