Dynamic neutrophil-keratinocyte communication network centered on IL-36/TNFSF15 responses characterizes inflammatory responses in generalized pustular psoriasis

Generalized pustular psoriasis (GPP) is a severe subtype of psoriasis characterized by epidermal neutrophil infiltration, often presenting as acute, potentially life-threatening flares. However, the characterization of the immune micro-environment in GPP lesions remains largely unknown. Here, we use single-cell RNA profiling to interrogate the transcriptomes of 60,000 single cells from GPP lesional skin (n = 13) and healthy adult skin (n = 4), combined with spatial transcriptomics. We identify a neutrophil subset lacking CASP8 expression but exhibiting elevated levels of inflammatory pathway genes, including RIPK1, NFKB1, IL1B, CXCL1, and CXCL8 in GPP flares, illustrating neutrophil transition from pre-inflammatory to a pro-inflammatory state, and activation of a communication network between IL36G+ keratinocytes and neutrophils in GPP lesions, with TNFSF15 (TL1A) released from neutrophils exaggerating the inflammatory crosstalk. We further demonstrate that fibroblasts and capillary endothelial cells function as central communication hubs in GPP, through dynamic receptor-ligand interactions with several spatially proximate immune cells, including T cells, neutrophils, and macrophages. In this work, we provide an in-depth view of immune cell participation and highlight the role of neutrophil-keratinocyte crosstalk in GPP pathogenesis.