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

Abstract

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. FASEB J. 33, 6813–6828 (2019). http://www.fasebj.org

Mononuclear Phagocyte Activation Is Associated With the Immunopathology of Psoriasis

“…Pustular psoriasis is a more inflammatory presentation of the disease where, besides mononuclear phagocytes, neutrophils plays important role in inflammation (39). However, it has been documented that TNF contribute to vulgar psoriasis presentation, considering that targeting TNF using biologics improves symptoms (40). Taken together, the results herein present convincing evidence of the deleterious role played by mononuclear phagocytes in the exacerbation of immunopathology, and suggest that the inhibition of the soluble products secreted by these cells may benefit psoriatic patients.…”

Exosome-based immunotherapy: a promising approach for cancer treatment

“…Proteomic and RNA microarray analyses indicate that neutrophil-derived exosomes contain proteins, mRNA and miRNAs, which are associated with inflammatory reactions, immune response and cell communication [134][135][136]. Functional studies further discover that neutrophil-derived exosomes can affect the activity of other immune cells, such as macrophages, by transferring several proinflammatory factors [137].…”

Extracellular vesicles in Inflammatory Skin Disorders: from Pathophysiology to Treatment

“…Neutrophil-EVs containing neutrophil elastase degraded the extracellular matrix, which exacerbated chronic obstructive pulmonary disease 91 . Moreover, we showed that neutrophil-EVs activated adjacent keratinocytes and increased the expression and production of pro-inflammatory mediators, which induced a vicious cycle in severe pustular psoriasis 82 . In addition, neutrophil-EVs exerted anti-inflammatory effects, such as reducing pro-inflammatory mediators to protect the cartilage 92 , inhibiting the production of pro-inflammatory cytokines and enhancing anti-inflammatory cytokines in NK cells 93 , monocyte-derived DCs 94 , or macrophages 95 - 97 , which indirectly limited excessive inflammatory responses.…”

“…Our recent study demonstrated that EVs isolated from psoriatic cytokine-induced keratinocytes could be endocytosed by neutrophils and induced the latter to produce NETs and pro-inflammatory cytokines, thus exacerbating psoriatic inflammation 12 . Interestingly, neutrophils from patients with generalized pustular psoriasis secreted more EVs than those from controls, and further triggered keratinocytes to produce high levels of inflammatory molecules, such as IL-1β, IL-36G, IL-18 and TNF-α 82 . These results suggest that EVs are critical mediators of keratinocyte-neutrophil crosstalk in the pathogenesis of psoriasis.…”