Cavagnero, K. J.; Albright, J.; Li, F.; Dokoshi, T.; Bogle, R.; Kirma, J.; Kahlenberg, J. M.; Billi, A. C.; Fox, J.; Coon, A.; Dobry, C. J.; Hinds, B.; Tsoi, L. C.; Harms, P. W.; Gudjonsson, J. E.; Gallo, R. L.

Sweet\'s syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweet\'s syndrome revealed a prominent interferon signature in Sweet\'s syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweet\'s syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweet\'s syndrome through recognition of type I interferons.