Yuqing Wang, Khashayar Afshari, Nazgol‐Sadat Haddadi, Carolina S. Lopes, Chee-Huat Linus Eng, Leah Whiteman, Núria Martínez, Pyae Phyo Kyawe, Ksenia S. Anufrieva, Kevin Wei, Kirsten L. Frieda, Misha Rosenbach, Ruth Ann Vleugels, Stefania Gallucci, John E. Harris, Mehdi Rashighi, Manuel Garber
Photosensitivity is central to cutaneous lupus erythematosus and dermatomyositis (DM), but the mechanisms linking UVB exposure to tissue-specific autoimmunity are poorly defined. Using single-cell RNA sequencing, spatial transcriptomics, proteomics, UVB provocation and in vitro modeling, we identify MMP9⁺CD14⁺ myeloid cells as critical mediators of photosensitivity. These cells expand significantly in lesional skin, produce interferon-β (IFNβ) and colocalize with cytotoxic CD4⁺ T cells at the dermal–epidermal junction. Keratinocytes activate fibroblasts in the superficial dermis, prompting them to release chemokines (CCL2, CCL19, CCL7, CCL8) that recruit MMP9⁺CD14⁺ cells. In vitro, type I interferon-primed keratinocytes exposed to UVB release cytokines activating dendritic cells, mirroring in vivo responses. UVB irradiation of non-lesional skin of patients with DM rapidly recruits these myeloid cells. In a clinical proof-of-concept study, anti-type I interferon treatment with anifrolumab prevented UVB-induced myeloid infiltration and reduced photosensitivity. Therefore, targeting MMP9⁺CD14⁺ cells may offer therapeutic potential for managing photosensitive autoimmune skin conditions. Wang, Afshari, Haddadi and colleagues compare UVB-sensitive and insensitive human skin diseases and show that photosensitive conditions, including cutaneous lupus erythematosus and dermatomyositis, have increased type I interferon activity and an expanded MMP9⁺CD14⁺ myeloid population that drives inflammation.