| Autor: |
Adrian Kobiela, Weronika Hewelt-Belka, Joanna E Frąckowiak, Natalia Kordulewska, Lilit Hovhannisyan, Aleksandra Bogucka, Rachel Etherington, Artur Piróg, Irena Dapic, Susanne Gabrielsson, Sara J Brown, Graham S Ogg, Danuta Gutowska-Owsiak |
| Rok vydání: |
2022 |
| DOI: |
10.21203/rs.3.rs-2365588/v1 |
| Popis: |
The promoting effect of FLG loss-of-function mutations on the development of atopic dermatitis (AD) signifies the role of filaggrin in the formation of a protective skin barrier; FLG mutations are also linked to asthma, food allergy and allergic rhinitis despite the absence of the protein in the affected tissues (lungs, intestines, and the majority of the nasal mucosa). AD patients suffer from chronic inflammation and recurrent skin infections; inflammation often precedes the appearance of spatially distant allergic manifestations. Here we show that exosome-enriched small extracellular vesicles (sEVs) secreted by filaggrin-knockdown keratinocytes are extensively remodelled as a consequence of the abnormal keratinocyte differentiation process. This alteration modulates the sEV capacity to promote type 1 and type 2 CD1a-dependent T cell responses by direct effects on self-lipid neoantigen generation; both modulating the amount of permissive (stimulatory) and non-permissive (inhibitory) CD1a ligands released from the sEV membranes by phospholipase A2. We found that this aberrant sEV lipid composition reflects a generalised cellular lipid bias with downregulation of multiple enzymes of lipid metabolic pathways, observed both in filaggrin knockdown keratinocytes in vitro, and in the skin of AD patients. Provision of modulatory ligands by sEVs secreted on a filaggrin insufficiency background, impeding both homeostatic autoreactive and protective antimicrobial CD1a-mediated type 1 and enhancing type 2 T cell responses provides basis for reduced tissue integrity and pathogen clearance and perpetuates inflammation in AD skin as well as in distant tissues to which sEVs are transferred by systemic circulation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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