Keratinocyte-neutrophil interactions revealed as targetable drivers of sustained inflammation in Sweet syndrome.

Abstract

Neutrophils are key drivers of inflammation in Sweet syndrome (SS), a rare inflammatory skin disorder, but how they remain persistently activated in SS skin lesions has been unclear. In this issue of the JCI, Huang, Sati, and colleagues applied single-cell RNA-Seq and immunofluorescence to identify a subset of neutrophils in SS skin that display antigen-presenting cell-like (APC-like) features. The authors showed that when neutrophils interacted with keratinocytes, their lifespan was markedly extended, and they expressed MHC class II via activation of the serum amyloid A1/formyl peptide receptor 2 (SAA1/FPR2) signaling pathway. This, in turn, enabled T cell activation and sustained self-perpetuating inflammatory loops. These findings reveal a previously unrecognized keratinocyte-neutrophil circuit in SS and point to the SAA1/FPR2 axis as a potential target for more precise, mechanism-based therapy.