Keratinocytes induce neutrophils to acquire antigen presentation capability in sweet syndrome

Summary: Abstract Body: Acute febrile neutrophilic dermatosis (Sweet syndrome) is characterized by erythematous plaques with a dense dermal neutrophilic infiltrate. Our prior work identified a molecular trigger to increase recruitment of neutrophils to skin but did not explain their prolonged persistence. We collected skin and blood from 10 Sweet syndrome patients and performed single-cell RNA-sequencing. Sweet syndrome skin was specifically enriched for a non-canonical population of antigen-presenting cell (APC)-like neutrophils (~25% of all neutrophils, p value = 0.0007). These neutrophils expressed canonical APC markers, including MHC-II complex genes, CD80, CD86, and CD40. Notably, this population was absent in Sweet syndrome blood, indicating a tissue-specific local activation. We validated this neutrophil population by immunofluorescence analysis of classical APC markers, including HLA-DPA and HLA-DRB, on 5 additional Sweet syndrome patient skin samples. Using an in vitro co-culture system, we demonstrated that keratinocyte-derived serum amyloid A1 (SAA1) binds to formyl peptide receptor 2 (FPR2) on neutrophils, to drive neutrophils to adopt this APC-like phenotype. APC-like neutrophils exhibited extended survival (52% viability at 72 hours versus 5% for conventional neutrophils, p value < 0.0001) and resistance to neutrophil extracellular trap formation. They also stimulated interferon-gamma production from T cells. Finally, established Sweet Syndrome therapeutics, including corticosteroids, reduced the extended survival of APC-like neutrophils. Taken together, we identify a novel keratinocyte-neutrophil pathway that explains the increased persistence of dermal neutrophils and improves our understanding of Sweet syndrome pathogenesis. Satish Sati¹, John Huang¹, Misha Rosenbach¹, Thomas Leung^{1, 2} 1. Dermatology, University of Pennsylvania, Philadelphia, PA, United States. 2. Corporal Michael J Crescenz VA Medical Center, Philadelphia, PA, United States. Cell Communication Networks and Stromal Biology