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<p>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<sup>+</sup>CD14<sup>+</sup> myeloid cells as critical mediators of photosensitivity. These cells expand significantly in lesional skin, produce interferon-β (IFNβ) and colocalize with cytotoxic CD4<sup>+</sup> 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<sup>+</sup>CD14<sup>+</sup> 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<sup>+</sup>CD14<sup>+</sup> cells may offer therapeutic potential for managing photosensitive autoimmune skin conditions.</p>

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A spatially coordinated keratinocyte–fibroblast circuit recruits MMP9+ myeloid cells to drive type I interferon-driven inflammation in photosensitive autoimmunity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月24日

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  • Yuqing Wang,
  • Khashayar Afshari,
  • Nazgol-Sadat Haddadi,
  • Carolina Salomão Lopes,
  • Chee-Huat Linus Eng,
  • Leah M. Whiteman,
  • Nuria Martinez,
  • Pyae P. Kyawe,
  • Ksenia S. Anufrieva,
  • Kevin Wei,
  • Kirsten Frieda,
  • Misha Rosenbach,
  • Ruth Ann Vleugels,
  • Stefania Gallucci,
  • John E. Harris,
  • Mehdi Rashighi,
  • Manuel Garber

摘要

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.