| Title: |
Interleukin‐8/Matrix Metalloproteinase‐9 Axis Impairs Wound Healing in Type 2 Diabetes through Neutrophil Extracellular Traps‐Fibroblast Crosstalk |
| Authors: |
Tsilingiris, Dimitrios; Natsi, Anastasia‐Maria; Gavriilidis, Efstratios; Antoniadou, Christina; Eleftheriadou, Ioanna; Anastasiou, Ioanna A.; Tentolouris, Anastasios; Papadimitriou, Evangelos; Eftalitsidis, Evgenios; Kolovos, Panagiotis; Tsironidou, Victoria; Giatromanolaki, Alexandra; Koffa, Maria; Tentolouris, Nikolaos; Skendros, Panagiotis; Ritis, Konstantinos |
| Source: |
European Journal of Immunology ; volume 55, issue 4 ; ISSN 0014-2980 1521-4141 |
| Publisher Information: |
Wiley |
| Publication Year: |
2025 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
Neutrophils interact with and activate fibroblasts through the release of neutrophil extracellular traps (NETs). We investigated the role of NETs‐fibroblast crosstalk in the cutaneous wound healing of type 2 diabetes (T2D). Neutrophils/NETs, serum, and primary human skin fibroblasts (HSFs) were obtained from individuals with T2D and age/sex‐matched controls. NET‐stimulation studies were performed on neutrophils/HSFs, with and without specific inhibitors, while HSF healing capacity was assessed using a scratch wound healing assay. T2D HSFs display a profibrotic phenotype, showing increased CCN2/CTGF, α‐smooth muscle actin, and collagen release, albeit with impaired healing capacity, elevated type I collagen C‐terminal telopeptide, and collagen degradation associated with increased (∼3.5‐fold) matrix metalloproteinase‐9 (MMP‐9) in T2D neutrophils/NETs. IL‐8 induced the expression of MMP‐9 in neutrophils/NETs. Moreover, T2D neutrophils/NETs exhibited increased IL‐8 content, which acted in an autocrine/paracrine fashion to further augment its production by neutrophils/HSFs. The findings were validated in normoglycemic individuals during a hyperglycemic clamp with concomitant lipid infusion and further corroborated immunohistochemically in diabetic plantar ulcer biopsies. This novel, vicious circle of NETs/interleukin‐8/MMP‐9/HSFs was hindered by IL‐8 or MMP‐9 blockade via specific inhibitors or by dismantling the NET‐scaffold with DNase I, suggesting candidate therapeutic targets in wound healing impairment of T2D. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1002/eji.202451664 |
| Availability: |
https://doi.org/10.1002/eji.202451664; https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.202451664 |
| Rights: |
http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.6651D6C5 |
| Database: |
BASE |