Positionally distinct interferon-stimulated dermal immune-acting fibroblasts promote neutrophil recruitment in Sweet syndrome.

Background: Sweet syndrome is an inflammatory skin disease characterized by robust neutrophil infiltration into the dermis. The pathogenesis of Sweet syndrome and its distinguishing features compared to other neutrophilic dermatoses, such as pyoderma gangrenosum, remain poorly understood.

Objective: Our aim was to define the cellular and molecular landscape of the skin of patients with Sweet syndrome.

Methods: Single-nucleus and bulk transcriptomics were performed on archival clinical skin samples from patients with Sweet syndrome, patients with pyoderma gangrenosum, and healthy controls. For mechanistic validation, functional experiments were performed with primary human cells. Spatial transcriptomics with single-molecule resolution was used to map cell types to tissue location.

Results: A prominent interferon signature was identified in Sweet syndrome skin that was reduced in tissue samples from patients with pyoderma gangrenosum and healthy controls. 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 dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, spatial transcriptomics revealed 2 positionally distinct interferon-activated fibroblast subsets: CXCL1-positive fibroblasts near neutrophil infiltrates and CXCL12-positive fibroblasts distal to these infiltrates.

Conclusion: This study defines the cellular and molecular landscape of neutrophilic dermatoses and implicates dermal immune-acting fibroblasts in Sweet syndrome pathogenesis through type I interferon recognition and neutrophil recruitment.