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

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

Objective: To define the cellular and molecular landscape of Sweet's syndrome skin.

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

Results: A prominent interferon signature was identified in Sweet's syndrome skin greater than in tissues from 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 two positionally distinct interferon-activated fibroblast subsets: CXCL1+ fibroblasts near neutrophil infiltrates and CXCL12+ 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's syndrome pathogenesis through type I interferon recognition and neutrophil recruitment.