SAA1/FPR2 signaling between keratinocytes and neutrophils sustains chronic inflammation in Sweet syndrome
Jianhe Huang, Satish Sati, Olivia Ahart, Emmanuel Rapp-Reyes, Linda Zhou, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung
Jianhe Huang, Satish Sati, Olivia Ahart, Emmanuel Rapp-Reyes, Linda Zhou, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung
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Research Article Dermatology Immunology

SAA1/FPR2 signaling between keratinocytes and neutrophils sustains chronic inflammation in Sweet syndrome

Abstract

Sweet syndrome (also known as acute febrile neutrophilic dermatosis) is a rare inflammatory skin disorder characterized by erythematous plaques with a dense dermal neutrophilic infiltrate. The first-line therapy remains oral corticosteroids, which suppresses inflammation nonspecifically. Although neutrophils are typically short-lived, how they persist in Sweet syndrome skin and contribute to disease pathogenesis remains unclear. Here, we identify a previously unrecognized population of antigen-presenting cell–like (APC-like) neutrophils expressing MHC class II genes that are uniquely present in Sweet syndrome skin but absent in healthy tissue and the circulation. Keratinocytes extended neutrophil lifespan 10-fold in coculture experiments and drove the emergence of an APC-like phenotype in approximately 30% of neutrophils, mirroring observations in patients’ lesions. Mechanistically, keratinocyte-derived serum amyloid A1 (SAA1) signals through the formyl peptide receptor 2 (FPR2) on neutrophils to promote their survival. These long-lived neutrophils actively orchestrate local immune responses by recruiting T cells and inducing cytokine production. Strikingly, dual blockade of SAA1/FPR2 signaling restores neutrophil turnover to baseline levels, with efficacy comparable to high-dose corticosteroids. These findings uncover a keratinocyte/neutrophil/T cell axis that sustains chronic inflammation in Sweet syndrome and highlight the SAA1/FPR2 pathway as a promising target for precision therapy.

Authors

Jianhe Huang, Satish Sati, Olivia Ahart, Emmanuel Rapp-Reyes, Linda Zhou, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung

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Figure 1

Immune cell landscape in Sweet syndrome.

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Immune cell landscape in Sweet syndrome. (A) H&E staining of affecte...
(A) H&E staining of affected and unaffected skin. (B) t-SNE plot depicting all cell clusters (n = 6 for affected and n = 5 for unaffected skin). (C) Marker genes defining cell types. Dot size reflects the percentage of cells expressing the gene, and color illustrates the level of gene expression. (D) t-SNE plot depicting immune cell subclusters. (E) Marker genes defining immune cell types. Dot size reflects the percentage of cells expressing the gene, and color illustrates the level of gene expression. (F) Decoding cell type specificity correlation plot for cell type enrichment analysis of different cell clusters. The y-axis shows the main cell types identified from the BlueprintEncode database. The color scale represents the Pearson correlation coefficient, and dot sizes represent the –log10-transformed P value. Prolif, proliferating. (G) Bar graph shows relative contribution of immune cell subtype as the percentage of total cells. Two-tailed, unpaired Student’s t test. *P < 0.05 and **P < 0.01 (H) Representative immunofluorescence staining of 4 diseased and 3 normal skin samples confirming populations of macrophages (CD68+), B cells (CD20+), and T cells : (CD3+, CD8+) in Sweet syndrome dermis. Scale bars: 100 μm. Avg. Exp., average expression; HSC, hematopoietic stem cells; pDC, plasmacytoid dendritic cells; Neut, neutrophil; LE, lymphatic endothelial; Mac, macrophage; SmMus, smooth muscle; VE, vascular endothelial.