Persistent CCL3 expression sustains neutrophil recruitment and contributes to delayed wound healing in advanced age

Delayed wound healing in advanced age is associated with prolonged inflammation, but the mechanisms that impair inflammatory resolution in this context remain poorly defined. Neutrophils are essential for early repair, but their persistence is predicted to disrupt resolution and delay healing. Here we show that aged mice exhibit impaired wound closure accompanied by sustained neutrophil infiltration from days 7-14 post-injury, long after neutrophils have resolved in young wounds. In aged skin, macrophage abundance and neutrophil-macrophage interactions were reduced, consistent with reduced macrophage-mediated clearance. Instead, neutrophils preferentially localised to perivascular regions, consistent with ongoing recruitment. Transcriptomic profiling demonstrated that young wounds transitioned from inflammatory to reparative programs, whereas aged wounds retained inflammatory signatures, including enrichment for neutrophil chemotaxis and LPS-response pathways. Notably, Ccl3, Cxcl2 and Cxcl3 remained elevated in aged wounds. Analysis of human chronic ulcers identified macrophages as a major source of these transcripts, and aged mouse wounds possessed more CCL3+ macrophages than in young. Targeted blockade of CCL3 beginning at day 4 post-injury reduced neutrophil accumulation, accelerated wound closure, and rescued key features of age-impaired healing, when administered after the initial inflammatory phase. Together, these findings identify persistent CCL3 expression as a contributor to sustained neutrophil recruitment and impaired repair in advanced age. Therapeutically targeting this pathway offers a strategy to restore timely resolution and improve healing outcomes.