Publications Repository - Gdańsk University of Technology

The association between FLG loss-of-function mutations and the development of atopic dermatitis (AD) indicates that filaggrin is critical to skin barrier function; the mutations are also linked to additional allergic manifestations, but it is unknown how the skin may influence inflammation in distant tissues. Here we investigated the impact of filaggrin insufficiency on keratinocyte-derived exosome-enriched small extracellular vesicles (sEVs) and found that those secreted by filaggrin-knockdown cells are extensively remodelled as a consequence of the abnormal keratinocyte differentiation process. The altered sEV lipidome changes the sEV capacity to promote T-cell responses by direct effect on self-lipid neoantigen generation, modulating the content of permissive (stimulatory) and nonpermissive (inhibitory) CD1a ligands released from the sEV membranes by phospholipase A2. Presentation of those lipids to T cells results in the redirection from a type 1 to a type 2 response. We found that the aberrant sEV lipid composition mirrors a generalized remodelling of cellular lipids resulting from dysregulated expression of multiple enzymes of lipid metabolic pathways, observed both in filaggrin knockdown keratinocytes in vitro and in the skin of patients with AD. Hence, filaggrin insufficiency background renders keratinocytes capable of supplying CD1a ligands which are capable of impeding both homeostasis-promoting and protective antimicrobial responses, enhancing type 2 T-cell activation to perpetuate inflammation in AD skin. sEV transfer by systemic circulation may promote similar effects in distant tissues.

Authors

• Adrian Kobiela,
• dr hab. inż. Weronika Hewelt-Belka link open in new tab ,
• Joanna Frackowiak,
• Natalia Kordulewska,
• Lilit Hovhannisyan,
• Aleksandra Bogucka,
• Rachel Etherington,
• Artur Pirog,
• Irena Dapic,
• Susanne Gabrielsson,
• Sara Brown,
• Graham Ogg,
• Danuta Gutowska-Owsiak