Diabetes-DB21-1108R_Supplemental_Figures.pdf (544.41 kB)
Download file

Inhibition of CCL28/CCR10-mediated eNOS Downregulation Improves Skin Wound Healing in the Obesity-induced Mouse Model of Type 2 Diabetes

Download (544.41 kB)
figure
posted on 28.07.2022, 11:50 authored by Zhenlong Chen, Jacob M. Haus, Lin Chen, Ying Jiang, Maria Sverdlov, Luisa A. DiPietro, Na Xiong, Stephanie C. Wu, Timothy J. Koh, Richard D. Minshall

Chronic, non-healing skin wounds such as diabetic foot ulcers (DFUs) are common in patients with type 2 diabetes. Here, we investigated the role of chemokine CCL28 and its receptor CCR10 in downregulation of endothelial nitric oxide synthase (eNOS) in association with delayed skin wound healing in the db/db mouse model of type 2 diabetes. We observed reduced eNOS expression and elevated CCL28/CCR10 levels in dorsal skin of db/db mice and subdermal leg biopsies from human subjects with type 2 diabetes. Further interrogation revealed that overexpression of CCR10 reduced eNOS expression, NO bioavailability, and tube formation of human dermal microvascular endothelial cells (HDMVECs) in vitro which was recapitulated in mouse dorsal skin. In addition, incubation of HDMVECs with CCL28 led to internalization of the CCR10/eNOS complex and co-localization with lysosome-associated membrane protein-1. Finally, topical application of myristoylated CCR10 binding domain 7 amino acid (Myr-CBD7) peptide prevented CCR10-eNOS interaction and subsequent eNOS downregulation, enhanced eNOS/NO levels, eNOS/VEGF-R2+ microvessel density, and blood perfusion, reduced inflammatory cytokine levels, and importantly, decreased wound healing time in db/db mice. Thus, endothelial cell CCR10 activation in genetically obese mice with type 2 diabetes promotes eNOS depletion and endothelial dysfunction, and targeted disruption of CCR10/eNOS interaction improves wound healing 

Funding

This work was supported in part by National Institutes of Health grants HL125356, HL142636 (RDM), DK109948 (JMH), and R35GM136228 (TJK), American Diabetes Association grant 1-14-JF-32 (JMH), CTSA UL1RR029879 sponsored pilot funding (RDM, TJK, JMH), and the Chancellor’s Translational Research Initiative at the University of Illinois at Chicago (RDM, ZC).

History