Macrophage Dicer1 deletion delays skin wound healing in mice by promoting pentose phosphate pathway activity.

BACKGROUND

Macrophages play a pivotal role in skin wound healing through efferocytosis, the clearance of apoptotic cells, which is essential for inflammation resolution and tissue repair. This study aims to investigate the role of macrophage Dicer1 in skin wound healing in mice and to explore the regulatory mechanism underlying efferocytosis.

METHODS

Dorsal skin wounds were created in Dicer1-deficient and wild type mice, and the wound areas were quantified daily. In the wounds, epithelialization, granulation tissue growth, collagen deposition, angiogenesis, and the mRNA levels of inflammatory cytokines were measured and apoptotic cells were labelled. In vitro, macrophages were separated from the wounds, and the expressions of pentose phosphate pathway (PPP)-related molecules were measured; wound macrophages were cocultured with apoptotic Jurkat cells, then the phagocytosis was analyzed, and the mRNA levels of inflammatory cytokines and PPP-related molecules were measured in the macrophages.

RESULTS

Macrophage-specific deletion of Dicer1 impairs skin wound healing in mice, resulting in delayed wound closure, reduced re-epithelialization and granulation tissue formation, diminished collagen deposition, and attenuated angiogenesis. Dicer1-deficient wounds exhibited sustained inflammation, alongside increased apoptotic cell accumulation. Mechanistically, Dicer1 knockout in macrophages led to impaired efferocytosis and upregulated PPP activity.

CONCLUSION

These findings identify the Dicer1-PPP-efferocytosis axis as a critical regulator of macrophage function during wound repair. Our study provides novel insights into the molecular basis of impaired wound healing and suggests that targeting the macrophage Dicer1-PPP-efferocytosis axis may offer therapeutic potential for skin wounds.