Role of various cytokines in the pathogenesis of diabetic foot ulcers.
| Cytokine/Pathway | Molecular and cellular effects | Mechanism |
|---|---|---|
| IL-6, IL-1β, TNF-α, IL-8 [43] | Prolongs inflammation, decreases angiogenesis, and alters ECM remodeling. Persistent inflammation, disruption of normal healing. | Pro-M1 activation (promotes inflammation). |
| TNF-α (↑), IL-10 (↓) [42] | Imbalance leads to innate immune defects.IL-10 secreted from Treg cells plays a role in M2 activation.Defective transition, prolonged M1 phase, little to no M2 involvement. | Imbalance prevents the M2 pathway from becoming activated and prolongs M1 activation. |
| NF-κB [44] | Master-regulatory Inflammatory pathway.Activation leads to increased TNF-α secretion.Prolonged inflammation and ECM degradation. | Activated by hyperglycemia, AGEs, and oxidative stress.Upregulates TNF-α, IL-1β, IL-6, and MMPs. |
| IFN-γ [45] | Prolongs inflammation Impaired wound healing | Stimulates TNF-α and IL-1β byMacrophages. |
| IFN-α/β [45] | Type I interferons are linked to impaired healing.Reduced angiogenesis and delayed granuloma formation. | Suppresses VEGF limits vascularization. |
| IFN-κ [46] | Promotes wound repair when restored.Accelerates closure in preclinical models. | Enhances re-epithelialization and collagen organization. |
| IL-6, IL-1β, TNF-α [43] | Inflammatory mediators linked to chronicity.Restores normal inflammatory timing and reduces chronic inflammation. | Prolonged cytokine peaks; NPWT shifts peak earlier. |
| TNF-α, IL-β, IL-6 [43] | ChronicM1 activation, inflammation, and delayed healing. | Persistent elevation leads to ECM degradation and a repair block. |
| IL-10, TGF-β, IGF-1 [44] | M2-associated markers: impaired angiogenesis, repair, and Treg promotion. | Suppressed in DFUs. |
AGEs: advanced glycation end products; DFUs: diabetic foot ulcers; ECM: extracellular matrix; IFN: interferon; IGF: insulin-like growth factor; IL: interleukin; MMPs: matrix metalloproteinases; NPWT: negative pressure wound therapy; TGF: transforming growth factor; TNF: tumor necrosis factor; VEGF: vascular endothelial growth factor.
AA: Writing—original draft. SM: Writing—original draft. HR: Writing—original draft. OB: Writing—original draft. VR: Writing—original draft, Writing—review & editing, Supervision. All authors read and approved the submitted version.
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