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The following is a summary of “Neutrophil extracellular traps activate Notch–γ-secretase signaling in hidradenitis suppurativa,” published in the September 2024 issue of Allergy and Immunology by Oliveira et al.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder characterized by painful, abscess-like nodules and boils, leading to tissue scarring and significant neutrophil infiltration, with potential links to Notch signaling pathway alterations yet to be fully understood.
Researchers conducted a retrospective study to elucidate the role of neutrophil extracellular traps (NETs) in Notch–γ-secretase signaling.
They analyzed 26 lesional tissues from patients with HS, along with primary HS macrophages and skin fibroblasts, using quantitative PCR, Western blot, and ELISA. They measured γ-secretase and TNF-α converting enzyme activities and performed immunofluorescence and RNAscope analyses in HS and control skin.
The results showed elevated levels of Notch ligands, Delta-like ligand 4 (DLL4), and Jagged (JAG)2, at both protein and mRNA levels in HS skin lesions compared to controls. DLL4, JAG1, citrullinated histone H3 DNA, and γ-secretase activity correlated with HS disease severity. Increased levels of Notch ligands and γ-secretase activity were found in dissected sinus tracts. Immunofluorescence microscopy indicated Notch-1 signaling activation in macrophages and skin fibroblasts within HS lesions. NETs from patients with HS showed elevated DLL4, activating the Notch pathway in macrophages and dermal fibroblasts. HS skin fibroblasts exhibited higher CD90 and DPP4 levels, which correlated with increased migratory capacity and Notch activation. Inhibition of Notch reduced migratory capacity and profibrotic markers in HS fibroblasts.
The study concluded that a pathogenic link exists between NETs, Notch–γ-secretase activation, and the release of profibrotic molecules, which contribute to the dysregulation of macrophages and skin fibroblasts in HS, highlighting potential targets for therapy.
Source: jacionline.org/article/S0091-6749(24)00911-4/abstract