Abstract

The pathogenesis of skin photodamage remains incompletely elucidated. Neutrophil extracellular traps (NETs) have been implicated in exacerbating skin photodamage. However, their precise mechanism requires further investigation. We detected NETs via immunofluorescence in skin tissues from patients with Actinic Dermatosis. In vivo, an acute photodamage mouse model was established by using UVB irradiation. Mice were treated with GSK484 (PAD4 inhibitor) and subjected to RNA-sequencing to explore the mechanism by which NETs promote inflammation and apoptosis. NETs content, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activity were assessed. In vitro, immortalized keratinocytes (HaCaT cells) were treated with NETs. Subsequently, cell viability, reactive oxygen species (ROS) levels, inflammatory cytokine release, apoptosis, SOD production, and MDA levels were measured. 25-pass transmembrane protein (CCDC25) was knocked down to validate its role as a critical receptor for NETs in HaCaT cells. As a result, abundant NETs were present in the skin of Actinic Dermatosis patients. Injection of GSK484 significantly alleviated UVB-induced skin damage, inflammation, and cell apoptosis in the mouse model. RNA-sequencing analysis revealed that peptidyl-arginine deiminase 4 (PAD4) deficiency inhibited UVB-induced mitogen-activated protein kinase (MAPK) activation. NETs treatment induced HaCaT cell apoptosis, suppressed cell viability, promoted inflammatory cytokine release, and disrupted redox homeostasis. NETs stimulation increased phospho-Jun-N-terminal kinase (p-JNK) activity. However, this activity was suppressed and cellular status was restored following CCDC25 knockdown. Collectively, NETs exacerbate skin photodamage by activating the p-JNK/JNK pathway via CCDC25, leading to HaCaT cell apoptosis, inhibition of cell viability, and the release of inflammatory cytokines.