Macrophage-derived IL-1β controls metabolic reprograming in distinct fibroblast progenitors to determine cell fate during wound healing

Compare with facial skin, oral mucosa has a high regenerative capacity and rapid healing efficiency, which has long been recognized as an ideal system of wound resolution. To decipher the underlying molecular mechanisms fostering this optimal healing process, we created a parallel injury model for both the oral and facial skin within the same mice. Utilizing single-cell transcriptomics (scRNA-seq) analysis, we were able to illuminate the diverse cell populations and the intricate cell-to-cell interactions taking place at a single cell level. Leveraging tools such as CytoTRACE, along with cell trajectory and RNA velocity analyses, we pinpointed fibroblast progenitors. Through the employment of GSEA and CellChat analyses, corroborated by flow cytometry and immunofluorescence staining, we demonstrated that IL-1β derived from macrophages augments oxidative phosphorylation in Il1rl1+ progenitors in skin. This points to a rapid response mechanism facilitated by heightened cell-cell interactions through IL-1β signals. We elucidated that the underlying mechanism involves a metabolic reprogramming in oral Il1rl1+ fibroblast progenitors driven by IL-1β/IL1R1, triggering the activation of the NFκB signaling pathway. This shift transitions the metabolic state from glycolysis to oxidative phosphorylation, favoring stem cell differentiation over proliferation and consequently accelerating wound healing in the oral mucosa.