Immunoinflammatory Profile of FGF-18, IL-35 and Glutamic Acid Decarboxylase in Patients With Diabetic Foot Ulcers

Diabetic foot ulcer (DFU) is a serious problem that may cause amputation of the lower extremities in patients with diabetes. The present research aimed to assess the localised tissue expression and potential immunoinflammatory crosstalk among fibroblast growth factor-18 (FGF-18), glutamic acid decarboxylase (GAD) and interleukin-35 (IL-35) in DFU compared to non-diabetic controls (NDCs), while also examining the systemic serum levels of FGF-18 and IL-35. Venous blood was collected from 80 patients with DFU and 100 NDC, and the concentrations of serum IL-35, FGF-18 and blood haemoglobin A1c (HbA1c) were analysed. Aseptically collected biopsy samples were obtained from FUs of 30 type 2 diabetes (T2D) patients and from accidental foot wounds of 30 NDC. Biopsies were preserved in formalin (10%) until paraffin blocks were prepared. The immunohistochemical methodology used antibodies specifically to identify tissue FGF-18, GAD and IL-35 in the soft tissue specimens. The tissue expression of FGF-18, IL-35 and GAD was significantly higher in DFU compared to NDC (p ≤ 0.0001), suggesting a strong localised immunoinflammatory role, whereas serum levels of FGF-18 and IL-35 remained statistically unchanged. Furthermore, significant positive correlations 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) indicate robust immunoinflammatory crosstalk. The marked and correlated elevation of FGF-18, IL-35 and GAD specifically within DFU tissue, without changes in serum levels of FGF-18 and IL-35, establishes a robust, compartmentalised immunoinflammatory axis that drives chronic pathology and presents novel targets for localised therapeutic intervention.