Transient immunostimulation with LPS promotes tissue repair in aged skin

Abstract Tissue repair is often hampered during aging. Worldwide, chronic wounds in elderly present a major challenge to the medical and socioeconomic infrastructure of societies. A comprehensive understanding of how the aging innate immune system impacts wound homeostasis is lacking. Here we employed the approach of immune modulation to restore disrupted wound repair in aged mice skin. We found that a short pulse of bacterial lipopolysaccharide (LPS) before wounding markedly accelerate tissue repair in aged mice, which – if non-primed – exhibit a defective epidermal wound closure. LPS priming induces rapid sealing of wounds, immune cell activity, keratinocyte responsiveness and their differentiation towards a newly reconstituted wound epithelium. Structural elements such as NETs composed of DNA and membrane protrusions derived from LPS-activated neutrophils and macrophages, respectively, reinforce physical skin barrier in aged wounds. The physical barrier established by LPS-primed innate immune cells subsequently facilitates epithelial tongue migration and adhesion of ECM-producing mesenchymal cells. Collectively, this not only prevents the invasion of pathogens into the restoring skin tissue after injury, but also averts the persistence of low-grade inflammation associated with aged wounds. These findings underscore the benefit of immune cell priming in promoting cellular interactions between innate immune cells and epithelial cells that consequently restores physical skin barrier and promote tissue repair.