Human cathelicidin LL-37 is a multifunctional antimicrobial peptide that exhibits
antimicrobial and immunomodulatory activities. LL-37 regulates skin barrier function
and was recently reported to activate autophagy in macrophages. Because autophagy
deficiency is associated with skin diseases characterized by a dysfunctional epidermal
barrier, we hypothesized that LL-37 might regulate the skin barrier through autophagy
modulation. We showed that LL-37 activated autophagy in human keratinocytes and three-dimensional
skin equivalent models as indicated by increases in LC3 puncta formation, decreases
in p62, and autophagosome and autolysosome formation. LL-37‒induced autophagy was
suppressed by P2X7 receptor, adenosine monophosphate‒activated protein kinase, and unc-51-like kinase
1 inhibitors, suggesting that the P2X7, adenosine monophosphate‒activated protein kinase, and unc-51-like kinase 1 pathways
are involved. Moreover, LL-37 enhanced the phosphorylation of adenosine monophosphate‒activated
protein kinase and unc-51-like kinase 1. In addition, LL-37‒mediated autophagy involves
the mechanistic target of rapamycin and MAPK pathways. Interestingly, the LL-37‒induced
distribution of tight junction proteins and improvement in the tight junction barrier
were inhibited in autophagy-deficient keratinocytes and keratinocytes and skin models
treated with autophagy inhibitors, indicating that the LL-37‒mediated tight junction
barrier is associated with autophagy activation. Collectively, these findings suggest
that LL-37 is a potential therapeutic target for skin diseases characterized by dysfunctional
autophagy and skin barriers.
Abbreviations:
AD (atopic dermatitis), AMPK (adenosine monophosphate‒activated protein kinase), Ca2+ (calcium ion), KC (keratinocyte), mTOR (mechanistic target of rapamycin), TER (transepithelial electrical resistance), TJ (tight junction), ULK1 (unc-51-like kinase 1)To read this article in full you will need to make a payment
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Supplementary References
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Article info
Publication history
Published online: November 28, 2022
Accepted:
October 18,
2022
Received in revised form:
September 30,
2022
Received:
May 6,
2022
accepted manuscript published online XXX; corrected proof published online XXXPublication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
