FC04 Dynamic KC-neutrophil-fibroblast communication network centred on IL-36/TNFSF15 responses characterizes inflammatory responses in generalized pustular psoriasis

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Abstract Generalized pustular psoriasis (GPP) is a severe psoriatic subtype characterized by epidermal neutrophil infiltration, often occurring in acute, potentially life-threatening episodes. However, the characterization of the immune microenvironment in GPP lesions compared with plaque psoriasis remains largely unknown. Here, we used 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 RNA sequencing. GPP was associated with major shifts in multiple cell populations, including, in particular, increased frequency of myeloid immune cells and supraspinous keratinocytes. We identified a unique myeloid-derived neutrophil subset characterized by the absence of CASP8. CASP8− neutrophils were accompanied by high expression of inflammatory pathway genes, including RIPK1, NF-KB1, IL1B, CXCL1, and CXCL8 in a stable disease state and were found at low levels in an inactive state in healthy skin. Spatial mapping of these genes illustrated the neutrophil transition from pre-inflammation to a pro-inflammation state through casting off CASP8. In silico and in vitro co-culture studies demonstrated that the communication network between IL36G+ spinous KCs and neutrophils is enlarged in the GPP lesions, with TNFSF15 (TL1A) released from neutrophils exaggerating the inflammatory crosstalk. While there was a slight increase in Th17 cells, there was greater prominence of CD8+ cytotoxic T cells highlighted by upregulated GZMB, CCL5, NKG7, and PRF1 expression, hinting at a cytotoxicity tendency rather than inflammation response in GPP lesions. Notably, a subset of S100A9+ fibroblasts in GPP was observed to contribute to the amplification of the GPP immune network through the transition to a pro-inflammatory state, connected by ligand–receptor interactions with other spatially proximate immune cells, including Th17 cells, CD8+ Tc cells, neutrophils, and IL1B+ macrophages. In sum, these data provide an in-depth view of immune cell participation and highlight the role of neutrophil–KC–fibroblast crosstalk in GPP pathogenesis.