Spatiotemporal transcriptomics deciphered neutrophil activated IL-36 as driver and effective therapeutic target in Sweet syndrome

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is characterized by painful erythematous plaques or nodules with diffuse infiltration of mature neutrophils in the dermis. Most patients respond well to systemic corticosteroids, except for a few resistant cases. SS may be idiopathic or triggered by trauma, infection, drugs, and immune disorders. The exact pathogenesis, pathophysiology and precise treatment options beyond corticosteroids remain unclear. We applied anti-IL-36R monoclonal antibody, Spesolimab, to treat two SS patients and achieved favorable outcomes, however, the molecular mechanism is unproved. Here, we applied spatiotemporal transcriptomics at single-cell resolution and multiplex immunofluorescence on the skin lesion and blood samples from SS patients before, during, and after anti-IL-36R treatment. Releasing of neutrophil extracellular traps (NETs) was observed in the distinct NETosis neutrophil lineage infiltrating SS lesions, which secreted neutrophil elastase to splice full-length IL-36 proteins into their active forms, amplifying the inflammatory signal. From spatial view, the co-localized niches of heterogenous maturation neutrophils and IL36RN+ differentiated keratinocytes were found at the interface of the epidermis and dermis. The heterogenous maturation neutrophil activated IL-36 signaling was considered as rapid inflammatory response and was eliminated after treatment. Meanwhile, CD8+ T cells were also recruited and participated in the interferon signaling interacted with keratinocytes and neutrophils in the SS lesion, which was considered as delayed inflammatory response. Overall, a forward loop consisting of keratinocytes, heterogenous maturation neutrophils and CD8+ T cells was constructed to decipher the potential pathogenesis of SS, and IL-36 activated by neutrophil elastase released from heterogenous maturation neutrophils was one of the drivers of the loop. Moreover, IL-36 signaling was confirmed as a novel and effective treatment target for SS, which may be served as an alternative option for corticosteroid-resistant cases as well as patients with contraindications.