<p>Peripheral nerve injury is a common condition that imposes a significant burden on both society and patients, remaining a key focus in basic research. IL-33, a member of the IL-1 family, plays an important role in tissue repair following various injuries. This study aims to investigate the role and mechanism of IL-33 in peripheral nerve regeneration. Transcriptome sequencing, Western blot, and immunofluorescence were used to examine the expression changes and cellular localization of IL-33 after sciatic nerve injury in mice. In a mouse sciatic nerve crush model, exogenous recombinant IL-33 was administered, and its effects on nerve fiber regeneration and functional recovery were assessed through morphological and behavioral analyses. Transcriptome sequencing and in vitro BMDMs culture were employed to explore the mechanism by which IL-33 promotes peripheral nerve regeneration. After sciatic nerve crush injury in mice, IL-33 expression was significantly upregulated from days 1 to 7 post-injury, primarily in Schwann cells. Intraperitoneal injection of IL-33 promoted axonal regeneration, enhanced remyelination of myelinated nerve fibers, prevented atrophy of the affected gastrocnemius muscle, and facilitated motor function recovery. IL-33 treatment significantly increased the gene expression and number of M2 macrophage in the injured nerve without affecting M0 and M1 macrophage populations. Macrophage ablation reduced the pro-regenerative effects of IL-33 on axonal regrowth. In vitro experiments confirmed that IL-33 promotes the polarization of BMDMs toward M2 macrophages. In summary, this study demonstrated up-regulated IL-33 promotes nerve regeneration and functional recovery at least partly through induction of M2 polarization of macrophage after peripheral nerve injury.</p>