Type I and II Interferon Signalling Characterizes the Transcriptional Landscape of Sweet Syndrome

Sweet syndrome (SS) is an autoinflammatory neutrophilic dermatosis characterized by abrupt-onset inflammatory skin lesions and systemic symptoms, yet its molecular pathogenesis remains incompletely defined. To delineate disease-specific inflammatory programmes, we performed NanoString-based transcriptomic analysis of SS skin lesions and compared them with healthy control skin and pyoderma gangrenosum, a related neutrophilic dermatosis. SS exhibited a distinct inflammatory transcriptional signature marked by robust upregulation of type I and II interferon–stimulated genes, including CXCL9, CXCL10, GBP1, GBP5, IFIT2 and IRF7, distinguishing SS from both control groups. Cell type deconvolution analysis revealed enrichment of dendritic cells, consistent with a prominent type I interferon-driven immune response. In parallel, SS lesions demonstrated altered immunoproteasome gene expression, with upregulation of immunoproteasome subunits PSMB8, PSMB9 and PSMB10 and downregulation of the constitutive subunit PSMB7 suggesting functional remodelling of proteasomal activity. Together, these findings support a model in which dendritic cell-driven interferon signalling promotes immunoproteasome remodelling and sustains neutrophilic inflammation in Sweet. This study identifies a prominent interferon signalling as a defining molecular feature of SS and highlights potential therapeutic opportunities within the interferon–JAK/STAT and proteasome pathways.