Excess filaggrin in keratinocytes is removed by extracellular vesicles to prevent premature death and this mechanism can be hijacked by Staphylococcus aureus in a TLR2‐dependent fashion

Abstract

Filaggrin (FLG) protein is indispensable for multiple aspects of the epidermal barrier function but its accumulation in a monomeric filaggrin form may initiate premature keratinocytes death; it is unclear how filaggrin levels are controlled before the formation of storing keratohyalin granules. Here we show that keratinocyte‐secreted small extracellular vesicles (sEVs) may contain filaggrin‐related cargo providing a route of eliminating excess filaggrin from keratinocytes; blocking of sEV release has cytotoxic effects on those cells. Filaggrin‐containing sEVs are found in plasma in both healthy individuals and atopic dermatitis patients. Staphylococcus aureus (S. aureus) enhances packaging and secretion of filaggrin‐relevant products within the sEVs for enhanced export via a TLR2‐mediated mechanism which is also linked to the ubiquitination process. This filaggrin removal system, preventing premature keratinocyte death and epidermal barrier dysfunction, is exploited by S. aureus which promotes filaggrin elimination from the skin that could help safeguard bacterial growth.

PRSS3/mesotrypsin as a putative regulator of the biophysical characteristics of epidermal keratinocytes in superficial layers

“…In the skin, pro-filaggrin and its processing enzyme, mesotrypsin, are almost exclusively detected within nonmitotic and differentiated keratinocytes situated in the epidermal granular and cornified layers 18 , 25 . Within NHEK cells, while Pro-FLG is minimally expressed even in undifferentiated states, as previously demonstrated 29 , this protein undergoes a significant upregulation upon the induction of differentiation facilitated by CaCl 2 . This induction prompts cells to exit the cell cycle 11 , accompanied by a flattened morphology (Fig.…”

State of the Art on the Role of Staphylococcus aureus Extracellular Vesicles in the Pathogenesis of Atopic Dermatitis

“…Kobiela et al [ 57 ] demonstrated that supernatants from S. aureus cultures hijack the EV secretion machinery of keratinocytes, increasing the content of filaggrin eliminated inside these vesicles. This would deplete the keratinocyte reservoir of this protein, which could possibly impair the antimicrobial functions of the epidermal layer, favoring bacteria colonization.…”

Exosomes: The emerging mechanisms and potential clinical applications in dermatology

“…Besides, Kobiela et al reported that S. aureus enhanced filaggrin loading into the keratinocyte exosome via a Toll-like receptor 2 (TLR2)-mediated mechanism. The filaggrin removal system protected the keratinocytes from keratinocyte premature death and epidermal barrier dysfunction and helped safeguard bacterial growth (34). Kobiela et al also reported that AD cytokines and C. albicans collaboratively changed the surface glycosylation pattern of keratinocyte exosomes to increase their interaction with DCs via inhibitory Siglec receptors (35).…”