Immune dysregulation in chronic diabetic wounds: therapeutic opportunities for healing reprogramming

Diabetic foot ulcers (DFUs) represent a devastating complication of diabetes mellitus, affecting approximately 25% of diabetic patients and contributing significantly to morbidity, mortality, and healthcare costs worldwide. Chronic non-healing wounds in diabetes are characterized by persistent inflammation, impaired immune cell function, and dysregulated cellular responses. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has emerged as a critical mediator of chronic inflammation and wound chronicity in diabetes. This comprehensive review examines the molecular mechanisms linking NLRP3 inflammasome activation, macrophage polarization dynamics, and wound healing impairment in diabetic conditions. We discuss how hyperglycemia-induced oxidative stress, advanced glycation end-products (AGEs), and mitochondrial dysfunction converge to activate the NLRP3 inflammasome, leading to caspase-1 activation, interleukin-1β (IL-1β) and IL-18 maturation, and gasdermin D (GSDMD)-mediated pyroptosis. The reciprocal relationship between inflammasome activation and macrophage polarization bias toward the pro-inflammatory M1 phenotype is explored, highlighting how this perpetuates a chronic inflammatory wound microenvironment. Additionally, we examine the role of neutrophil extracellular traps (NETs) in amplifying inflammasome-mediated inflammation. Emerging therapeutic strategies targeting the NLRP3 inflammasome pathway are reviewed, including pharmacological inhibitors (MCC950, glyburide, disulfiram), natural compounds (quercetin, resveratrol, tanshinone IIA), and advanced biomaterial-based approaches. The potential for macrophage phenotype reprogramming through metabolic intervention and the integration of inflammasome modulation with tissue engineering strategies are discussed. Understanding the intricate crosstalk between NLRP3 inflammasome activation and macrophage polarization provides a foundation for developing targeted therapies that can reprogram the diabetic wound microenvironment from a chronic inflammatory state toward effective healing resolution.