Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds

Abstract

Although impaired keratinocyte migration is a recognized hallmark of chronic wounds, the molecular mechanisms underpinning impaired cell movement are poorly understood. Here, we demonstrate that both diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) exhibit global deregulation of cytoskeletal organization in genomic comparison to normal skin and acute wounds. Interestingly, we found that DFUs and VLUs exhibited downregulation of ArhGAP35, which serves both as an inactivator of RhoA and as a glucocorticoid repressor. Since chronic wounds exhibit elevated levels of cortisol and caveolin-1 (Cav1), we posited that observed elevation of Cav1 expression may contribute to impaired actin-cytoskeletal signaling, manifesting in aberrant keratinocyte migration. We showed that Cav1 indeed antagonizes ArhGAP35, resulting in increased activation of RhoA and diminished activation of Cdc42, which can be rescued by Cav1 disruption. Furthermore, we demonstrate that both inducible keratinocyte specific Cav1 knockout mice, and MβCD treated diabetic mice, exhibit accelerated wound closure. Taken together, our findings provide a previously unreported mechanism by which Cav1-mediated cytoskeletal organization prevents wound closure in patients with chronic wounds.

Proteomics changes after negative pressure wound therapy in diabetic foot ulcers

“…The GO enrichment analysis performed in the present study was consistent with a number of previous studies showing that the wound healing process of diabetic ulcers is associated with altered extracellular matrix deposition ( 20 ), cytoskeletal deregulation ( 21 ), dyslipidemia ( 22 ) and prolonged inflammation response ( 23 ). The present study unexpectedly found some signaling pathways that seemed weakly relevant to the curative effect of wounds in the enrichment analysis of KEGG signaling pathways, such as thyroid hormone synthesis, thyroid hormone signaling pathway, human T-cell leukemia virus 1 infection and African trypanosomiasis.…”

Frontiers in Lichen Planopilaris and Frontal Fibrosing Alopecia Research: Pathobiology Progress and Translational Horizons

“…If the proposed role for caveolins in FFA pathogenesis ( Jozic et al., 2021b ) is confirmed, this warrants investigation whether topical perturbation of intrafollicular CAV1, either pharmacologically (e.g., through cyclodextrins/statins) ( Jozic et al., 2021a , 2019 ; Sawaya et al., 2019 ) or by nanoparticle-mediated small interfering RNA delivery, can halt the—often relentless—progression of FFA/LPP and can be used as an auxiliary therapy to the other candidate therapeutics discussed in this paper. Interestingly, the OR2AT4 agonist, Sandalore, which prolongs anagen ex vivo ( Chéret et al., 2018 ), also downregulates the expression of CAV1 at both mRNA and protein levels ( Chéret et al., 2020 ; Jozic et al., 2021b ).…”

Dichotomous role of miR193b-3p in diabetic foot ulcers maintains inhibition of healing and suppression of tumor formation

“…We identified a mechanism of miR193b-3p antimigratory activity via the disruption of stress fiber formation, the actin structures fundamental for cell motility ( 62 , 63 ). Activation of small GTPase RhoA directly leads to stress fiber formation ( 64 ).…”