Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis via activating keratinocytes

Generalized pustular psoriasis (GPP) is a rare and severe inflammatory skin disease that can be life-threatening. Gene mutations are found in some cases, but its immune pathogenesis is largely unknown. Here, we observed that the neutrophil:lymphocyte ratio in patients with GPP was higher than that in healthy controls and decreased after effective treatment. Neutrophils isolated from patients with GPP induced higher expressions of inflammatory genes including IL-1β, IL-36G, IL-18, TNF-α, and C-X-C motif chemokine ligands in keratinocytes than normal neutrophils did. Moreover, neutrophils from patients with GPP secreted more exosomes than controls, which were then rapidly internalized by keratinocytes, increasing the expression of these inflammatory molecules via activating NF-κB and MAPK signaling pathways. The proteomic profiles in neutrophil exosomes further characterized functional proteins and identified olfactomedin 4 as the critical differentially expressed protein that mediates the autoimmune inflammatory responses of GPP. These results demonstrate that neutrophil exosomes have an immune-regulatory effect on keratinocytes, which modulates immune cell migration and autoinflammation in GPP.-Shao, S., Fang, H., Zhang, J., Jiang, M., Xue, K., Ma, J., Zhang, J., Lei, J., Zhang, Y., Li, B., Yuan, X., Dang, E., Wang, G. Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis via activating keratinocytes.