Keratinocyte-neutrophil interactions revealed as targetable drivers of sustained inflammation in Sweet syndrome
Umi Tahara, Masayuki Amagai
Umi Tahara, Masayuki Amagai
Published October 15, 2025
Citation Information: J Clin Invest. 2025;135(20):e198494. https://doi.org/10.1172/JCI198494.
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Commentary

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.

Authors

Umi Tahara, Masayuki Amagai

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Figure 1

SAA1/FPR2 signaling prolongs neutrophil survival and provides a therapeutic target in SS.

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SAA1/FPR2 signaling prolongs neutrophil survival and provides a therapeu...
(A) The keratinocyte-neutrophil interaction that occurs in SS skin, as reported by Huang, Sati, and colleagues (10). Keratinocytes, the predominant epidermal cell type, upregulate SAA1 in response to neutrophil interaction. Keratinocyte-derived SAA1 binds FPR2 on neutrophils, activating MAPK/ERK and PI3K/AKT signaling to inhibit apoptosis and extend neutrophil lifespan. This interaction maintains a pool of long-lived neutrophils, including a subset with APC-like features such as MHC II expression. Lesional neutrophils also produce CXCL10 and CXCL11, recruiting T cells that generate IL-17, linking neutrophil activity to Th17-type inflammation. (B) The effect of SAA1/FPR2 blockade. Blocking SAA1/FPR2 signaling with neutralizing antibodies promotes neutrophil apoptosis, thereby reducing the neutrophils’ survival. This axis represents a potential point of therapeutic intervention for SS.