TY - JOUR
T1 - Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds
AU - Jozic, Ivan
AU - Abujamra, Beatriz Abdo
AU - Elliott, Michael H.
AU - Wikramanayake, Tongyu C.
AU - Marjanovic, Jelena
AU - Stone, Rivka C.
AU - Head, Cheyanne R.
AU - Pastar, Irena
AU - Kirsner, Robert S.
AU - Andreopoulos, Fotios M.
AU - Musi, Juan P.
AU - Tomic-Canic, Marjana
N1 - Funding Information:
We are grateful to Timothy Thompson for providing us with Cav1-flox/flox mice that were used to generate tamoxifen-inducible K14-Cre Cav1KO mice. We are also very grateful to Ralf Paus for his generosity in sharing laboratory equipment. This work was funded in part by PhRMA Foundation Research Starter Grant, Medline Wound Healing Foundation Innovation Grant, Stanley J. Glaser Research Award (to I.J.); Organogenesis Inc. Research Grant (to M.T.C. and I.J.), SAC-2013-19, NR015649, DK119085, AR073614, U01DK119085, 32307-50 sub-award to U24DK115255 (to M.T.C.), SAC-2016-9R1, U01DK119085-02S1 (to R.C.S.), Oklahoma Center for Adult Stem Cell Research, NIH R01 EY019494 (to M.H.E.), University of Miami IAC Research Support Award 2021-3 and Dermatology Gift Fund, Dr. Phillip Frost Department fo Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine (to TCW), NEI Core P30EY021725, Dwoskin family gift and Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-021-02298-5
DO - 10.1038/s42003-021-02298-5
M3 - Article
C2 - 34145387
AN - SCOPUS:85108155613
VL - 4
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 757
ER -