Positionally distinct interferon-stimulated dermal immune-acting fibroblasts drive neutrophil recruitment in Sweet’s syndrome 4440

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Abstract Description Sweet’s syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archived FFPE clinical samples revealed elevated plasmacytoid dendritic cells and a prominent interferon signature in Sweet’s syndrome skin that was reduced in tissue from other neutrophilic dermatoses (pyoderma gangrenosum and pustular psoriasis) and healthy controls. Interferon-stimulated genes were highly expressed in subsets of fibroblasts, keratinocytes, lymphocytes, and myeloid cells. Functionally, cultured primary human dermal fibroblasts highly expressed neutrophil chemokines in response to type I but not type II interferon. Subcellular resolution spatial transcriptomics of archived FFPE clinical samples from neutrophilic dermatoses and healthy skin was leveraged to locate these immune-acting fibroblasts. This approach identified two positionally distinct immune-acting fibroblast subsets in Sweet’s syndrome: a CXCL1+ subset proximal to the neutrophilic infiltrate in the upper dermis and a CXCL12+ subset in the lower dermis distal to neutrophils. Thus, this study defines the cellular landscape of neutrophilic dermatoses and identifies dermal immune-acting fibroblasts with a pathogenic role in Sweet’s syndrome through recognition of type I interferon and neutrophil chemoattraction. Funding Sources Supported by NSF GRFP2038238, NIH T32DK007202, NIH R01DK121760, NIH R01AR076082, NIHR01AI153185, U01AI152038, P50AR080594, and NIH R37AI052453. Topic Categories Immune Mechanisms of Human Disease (HUM)

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