FGF-18, IL-35, and GAD Show Robust Localized Immunoinflammatory Role in Diabetic Foot Ulcers
Background
Diabetic foot ulcers (DFU) represent a severe complication of diabetes, often leading to lower limb amputations and imposing substantial healthcare burdens. Despite their prevalence, the precise localized immunoinflammatory drivers within DFU tissue, distinct from systemic inflammation, remain incompletely understood. Current standard-of-care often focuses on systemic management and wound care, but a deeper understanding of the specific tissue-level molecular environment could unlock more targeted therapeutic strategies. This study investigates the localized expression and interplay of fibroblast growth factor-18 (FGF-18), interleukin-35 (IL-35), and glutamic acid decarboxylase (GAD) within DFU tissue.
Study Design
Researchers conducted a comparative study involving 80 patients with DFU and 100 non-diabetic controls (NDCs) for serum analysis, alongside 30 type 2 diabetes (T2D) patients with FUs and 30 NDCs with accidental foot wounds for tissue biopsy analysis. Venous blood samples were collected to measure serum levels of IL-35, FGF-18, and HbA1c using ELISA assays. Aseptically collected biopsy samples from ulcer tissues and control wounds were preserved in formalin, processed into paraffin blocks, and then analyzed using immunohistochemistry with specific antibodies to identify tissue expression of FGF-18, GAD, and IL-35 in soft tissue specimens.
Results
The study revealed a marked and compartmentalized immunoinflammatory profile within DFU tissue. Tissue expression of FGF-18, IL-35, and GAD was significantly higher in DFU patients compared to NDCs, with a robust statistical significance (p ≤ 0.0001). This localized elevation suggests a strong, specific role for these biomarkers in the pathology of DFU. In contrast, systemic serum levels of FGF-18 and IL-35 showed no statistically significant changes between DFU patients and controls, highlighting the tissue-specific nature of these findings. Furthermore, significant positive correlations were observed between tissue IL-35 and FGF-18 (r = 0.67, p ≤ 0.05) and between tissue IL-35 and GAD (r = 0.60, p ≤ 0.05).
Key Findings
- Tissue expression of FGF-18, IL-35, and GAD was significantly elevated in DFU compared to non-diabetic controls (p ≤ 0.0001).
- Serum levels of FGF-18 and IL-35 remained statistically unchanged, indicating a localized immunoinflammatory response.
- Tissue IL-35 positively correlated with tissue FGF-18 (r = 0.67, p ≤ 0.05).
- Tissue IL-35 also positively correlated with tissue GAD (r = 0.60, p ≤ 0.05).
- A robust, compartmentalized immunoinflammatory axis involving these three biomarkers drives DFU pathology.
Why It Matters
This research significantly advances our understanding of the localized immunoinflammatory mechanisms driving Diabetic Foot Ulcers, identifying a distinct tissue-specific axis involving FGF-18, IL-35, and GAD. The findings suggest that targeting these specific biomarkers within the ulcer microenvironment could offer novel therapeutic avenues, moving beyond broad-spectrum anti-inflammatory approaches. For clinicians and researchers, this opens the door to developing localized interventions that could potentially accelerate healing and reduce amputation rates. Instead of solely focusing on systemic inflammation, future protocols might incorporate topical or intralesional therapies designed to modulate these specific pathways, offering a more precise and effective strategy for DFU management.
diabetic foot ulcer
inflammation
biomarkers
fgf-18
il-35
gad