Reduced Bioactive Microbial Products (PAMPs) Contribute to Dysregulated Immune Responses And Impaired Healing in Infected Wounds in Diabetic Mice

Diabetic chronic ulcers are plagued with persistent non-resolving inflammation. However, diabetic wound environment early after injury suffers from inadequate inflammatory responses due to reductions the 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 (PAMPs), which in turn contribute to reduced signaling through TLRs, 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, TLR4-mediated signaling is reduced in diabetic wound early after injury, due to reduced bioactive levels of lipopolysaccharide (LPS). We further demonstrate that topical treatment with LPS enhances TLR4 signaling, increases proinflammatory cytokine production, restores leukocytes trafficking, reduces infection burden, and stimulates healing in diabetic wound. We posit that LPS 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.