CCL3 and LPS combination therapy significantly reduces infection and stimulates wound healing in diabetic mice by boosting proinflammatory responses.

In contrast to chronic diabetic ulcers that are trapped in persistent heightened inflammation, diabetic wounds early after injury suffer from inadequate inflammatory responses. We previously identified defective chemotactic response in diabetic neutrophils, due to reduced signaling through the formyl peptide receptor, and diminished bioactive/bioavailable bacterial products (pathogen-associated molecular patterns), resulting from impaired bactericidal functions in diabetic neutrophils, as major culprits contributing to early inadequate inflammatory responses in diabetic wounds. Our prior work showed that topical treatments with either CCL3, a chemokine targeting auxiliary chemokine receptors to restore neutrophil trafficking, or lipopolysaccharide (LPS), a bacterial product to activate toll-like receptor, improved infection control and promoted healing by jumpstarting inflammatory responses early in diabetic wounds during the acute phase of healing. In this study, we evaluated whether combining CCL3 and LPS offers greater therapeutic benefit than either CCL3 or LPS alone. Our data show that CCL3 + LPS combination therapy was significantly more effective in reducing infection and enhancing wound healing than CCL3 or LPS monotherapies in db/db type 2 diabetic mouse model. We propose that topical application of CCL3 + LPS after surgical debridement-when chronic wounds are reset into an acute state-may offer a viable therapeutic approach for improving outcomes in diabetic wound care.