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

  • Nat Immunol. 2026 Jun;27(6):1184-1196. doi: 10.1038/s41590-026-02502-w.
Yuqing Wang  #  1 ,  Khashayar Afshari  #  2 ,  Nazgol-Sadat Haddadi  #  2 ,  Carolina Salomão Lopes  1 ,  Chee-Huat Linus Eng  3 ,  Leah M Whiteman  4 ,  Nuria Martinez  2 ,  Pyae P Kyawe  2 ,  Ksenia S Anufrieva  5 ,  Kevin Wei  5 ,  Kirsten Frieda  3 ,  Misha Rosenbach  6 ,  Ruth Ann Vleugels  7 ,  Stefania Gallucci  4 ,  John E Harris  2 ,  Mehdi Rashighi  8 ,  Manuel Garber  9
Affiliations
  • 1. Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 2. Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 3. Spatial Genomics, Pasadena, CA, USA.
  • 4. Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 5. Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital at Harvard Medical School, Boston, MA, USA.
  • 6. Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA.
  • 7. Department of Dermatology, Brigham and Women's Hospital at Harvard Medical School, Boston, MA, USA.
  • 8. Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, USA. [email protected].
  • 9. Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA. [email protected].
  • # Contributed equally.
PMID: 42032302 DOI: 10.1038/s41590-026-02502-w
Abstract

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.

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