Reduced Bioactive Microbial Products (Pathogen-Associated Molecular Patterns) Contribute to Dysregulated Immune Responses and Impaired Healing in Infected Wounds in Mice with Diabetes

Abstract

Diabetic chronic ulcers are plagued with persistent nonresolving inflammation. However, diabetic wound environment early after injury suffers from inadequate inflammatory responses due to reductions in proinflammatory cytokines levels. Diabetic neutrophils have known impairments in bactericidal functions. We hypothesized that reduced bacterial killing by diabetic neutrophils, due to their bactericidal functional impairments, results in reduced bioactive bacterial products, known as pathogen-associated molecular patterns, which in turn contribute to reduced signaling through toll-like receptors, leading to inadequate production of proinflammatory cytokines in infected diabetic wound early after injury. We tested our hypothesis in db/db type 2 obese diabetic mouse wound infection model with Pseudomonas aeruginosa. Our data indicate that despite substantially higher levels of infection, toll-like receptor 4-mediated signaling is reduced in diabetic wounds early after injury owing to reduced bioactive levels of lipopolysaccharide. We further demonstrate that topical treatment with lipopolysaccharide enhances toll-like receptor 4 signaling, increases proinflammatory cytokine production, restores leukocyte trafficking, reduces infection burden, and stimulates healing in diabetic wounds. We posit that lipopolysaccharide may be a viable therapeutic option for the treatment of diabetic foot ulcers if it is applied topically after the surgical debridement process, which is intended to reset chronic ulcers into acute fresh wounds.