Claudin targeting as an effective tool for directed barrier modulation of the viable epidermis
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Claudin targeting as an effective tool for directed barrier modulation of the viable epidermis. / Beier, Laura-Sophie; Waldow, Ayk; Khomeijani Farahani, Saeed; Mannweiler, Roman; Vidal-Y-Sy, Sabine; Brandner, Johanna M; Piontek, Jörg; Günzel, Dorothee.
In: ANN NY ACAD SCI, Vol. 1517, No. 1, 11.2022, p. 251-265.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Claudin targeting as an effective tool for directed barrier modulation of the viable epidermis
AU - Beier, Laura-Sophie
AU - Waldow, Ayk
AU - Khomeijani Farahani, Saeed
AU - Mannweiler, Roman
AU - Vidal-Y-Sy, Sabine
AU - Brandner, Johanna M
AU - Piontek, Jörg
AU - Günzel, Dorothee
N1 - © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.
PY - 2022/11
Y1 - 2022/11
N2 - Tight junction (TJ) formation is vital for epidermal barrier function. We aimed to specifically manipulate TJ barriers in the reconstructed human epidermis (RHE) by claudin-1 and -4 knockdown (KD) and by claudin-binding fusion proteins of glutathione S-transferase and modified C-terminal fragments of Clostridium perfringens enterotoxin (GST-cCPE). Impedance spectroscopy and tracer permeability imaging were employed for functional barrier assessment and investigation of claudin contribution. KD of claudin-1, but not claudin-4, impaired the paracellular barrier in vitro. Similarly, claudin-binding GST-cCPE variants weakened the paracellular but not the stratum corneum barrier. Combining both TJ targeting methods, we found that claudin-1 targeting by GST-cCPE after claudin-4 KD led to a marked decrease in paracellular barrier properties. Conversely, after claudin-1 KD, GST-cCPE did not further impair the barrier. Comparison of GST-cCPE variants with different claudin-1/claudin-4 affinities, NHS-fluorescein tracer detection, and immunostaining of RHE paraffin sections showed that GST-cCPE variants bind to extrajunctional claudin-1 and -4, which are differentially distributed along the stratum basale-stratum granulosum axis. GST-cCPE binding blocks these claudins, thereby specifically opening the paracellular barrier of RHE. The data indicate a critical role for claudin-1 in regulating paracellular permeability for ions and small molecules in the viable epidermis. Claudin targeting is presented as a proof-of-concept for precise barrier modulation.
AB - Tight junction (TJ) formation is vital for epidermal barrier function. We aimed to specifically manipulate TJ barriers in the reconstructed human epidermis (RHE) by claudin-1 and -4 knockdown (KD) and by claudin-binding fusion proteins of glutathione S-transferase and modified C-terminal fragments of Clostridium perfringens enterotoxin (GST-cCPE). Impedance spectroscopy and tracer permeability imaging were employed for functional barrier assessment and investigation of claudin contribution. KD of claudin-1, but not claudin-4, impaired the paracellular barrier in vitro. Similarly, claudin-binding GST-cCPE variants weakened the paracellular but not the stratum corneum barrier. Combining both TJ targeting methods, we found that claudin-1 targeting by GST-cCPE after claudin-4 KD led to a marked decrease in paracellular barrier properties. Conversely, after claudin-1 KD, GST-cCPE did not further impair the barrier. Comparison of GST-cCPE variants with different claudin-1/claudin-4 affinities, NHS-fluorescein tracer detection, and immunostaining of RHE paraffin sections showed that GST-cCPE variants bind to extrajunctional claudin-1 and -4, which are differentially distributed along the stratum basale-stratum granulosum axis. GST-cCPE binding blocks these claudins, thereby specifically opening the paracellular barrier of RHE. The data indicate a critical role for claudin-1 in regulating paracellular permeability for ions and small molecules in the viable epidermis. Claudin targeting is presented as a proof-of-concept for precise barrier modulation.
KW - Humans
KW - Claudins/metabolism
KW - Claudin-1/metabolism
KW - Claudin-4/metabolism
KW - Epidermis/metabolism
KW - Permeability
KW - Tight Junctions/metabolism
KW - Claudin-5/metabolism
U2 - 10.1111/nyas.14879
DO - 10.1111/nyas.14879
M3 - SCORING: Journal article
C2 - 35994210
VL - 1517
SP - 251
EP - 265
JO - ANN NY ACAD SCI
JF - ANN NY ACAD SCI
SN - 0077-8923
IS - 1
ER -