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

doi:10.1172/JCI193566

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

Jianhe Huang,¹ Satish Sati,¹ Olivia Ahart,¹ Emmanuel Rapp-Reyes,¹ Linda Zhou,¹ Robert G. Micheletti,¹ William D. James,¹ Misha Rosenbach,¹ and Thomas H. Leung¹

Published August 19, 2025 - More info

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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. First-line therapy remains oral corticosteroids, which suppresses inflammation non-specifically. 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 (APC)-like neutrophils expressing MHC class II genes that are uniquely present in Sweet syndrome skin but absent from healthy tissue and circulation. Keratinocytes extended neutrophil lifespan 10-fold in co-culture experiments and drove the emergence of an APC-like phenotype in approximately 30% of neutrophils, mirroring observations in patient 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.

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

Jianhe Huang,¹ Satish Sati,¹ Olivia Ahart,¹ Emmanuel Rapp-Reyes,¹ Linda Zhou,¹ Robert G. Micheletti,¹ William D. James,¹ Misha Rosenbach,¹ and Thomas H. Leung¹

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

Jianhe Huang,1 Satish Sati,1 Olivia Ahart,1 Emmanuel Rapp-Reyes,1 Linda Zhou,1 Robert G. Micheletti,1 William D. James,1 Misha Rosenbach,1 and Thomas H. Leung1

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Jianhe Huang,¹ Satish Sati,¹ Olivia Ahart,¹ Emmanuel Rapp-Reyes,¹ Linda Zhou,¹ Robert G. Micheletti,¹ William D. James,¹ Misha Rosenbach,¹ and Thomas H. Leung¹