Comparative multi-omics highlights inflammatory monocyte-derived dendritic cells as key mediators of UVB-induced photosensitivity

Summary: Abstract Body: Ultraviolet (UV) radiation presents a paradox in inflammatory skin biology: while widely used to treat conditions like psoriasis, it exacerbates diseases such as cutaneous lupus erythematosus (CLE) and dermatomyositis (DM). The mechanisms behind these divergent responses remain unclear. To address this, we conducted a systematic, multi-omics analysis—integrating proteomics, single-cell RNA sequencing, and spatial transcriptomics—comparing two photosensitive disorders (CLE and DM) to two photoresponsive conditions (psoriasis and vitiligo). Our findings identify monocyte-derived dendritic cells (moDCs) as central mediators of photosensitivity. In CLE and DM, moDCs are enriched in lesional skin, colocalizing with cytotoxic CD4+ T cells in the superficial dermis and expressing high levels of MMP9, a matrix metalloproteinase that degrades collagen IV at the dermo-epidermal junction. This degradation facilitates immune cell infiltration and amplifies interface dermatitis. In vitro, keratinocytes preconditioned with IFN-β displayed heightened susceptibility to UVB-induced cell death, releasing supernatants that activated moDCs and triggered chemokine production (e.g., CCL2, CCL7, CCL8). This established a positive feedback loop of moDC recruitment, IFN-β amplification, and cytotoxic T cell-driven tissue damage. Our findings highlight the pivotal role of moDCs and MMP9 in driving photosensitivity through a positive feedback loop that involves extracellular matrix remodeling, lymphocyte and immune cell recruitment and activation of recruited cells. Targeting MMP9 or disrupting moDC recruitment pathways offers a promising therapeutic approach to mitigate UV-induced inflammation in photosensitive dermatoses. Khashayar Afshari¹, Yuqing Wang¹, Nazgol Haddadi¹, Carolina S. Lopes¹, Chee-Huat L. Eng², Nuria Martinez-Gutierrez¹, Leah Whiteman¹, Ksenia S. Anufrieva³, Kevin Wei³, Kirsten Frieda², Stefania Gallucci¹, Misha Rosenbach⁴, Ruth Ann Vleugels³, John E. Harris¹, Manuel Garber¹, Mehdi Rashighi¹ 1. University of Massachusetts Chan Medical School, Worcester, MA, United States. 2. Spatial Genomics, Pasadena, CA, United States. 3. Brigham and Women's Hospital, Boston, MA, United States. 4. University of Pennsylvania, Philadelphia, PA, United States. Adaptive and Auto-Immunity