Role of IL-33 in Upregulating AREG Production During Wound Healing.

OBJECTIVE

IL-33 plays an important role in regulating immune responses and tissue repair; however, the specific mechanisms of IL-33 in wound healing, particularly in activating regulatory T cells (Tregs), remain unclear. This study aimed to investigate the role of IL-33 in promoting wound healing by regulating amphiregulin (AREG) production in Treg cells.

METHODS

Kunming mice and Areg knockout (Areg-/-) mice were used to establish full-thickness skin wound models. Recombinant mouse IL-33 (rmIL-33) was administered intranasally or intradermally to assess wound healing dynamics. Wound tissues were analyzed via hematoxylin-eosin (HE) staining, Masson's trichrome staining, flow cytometry, quantitative real-time PCR (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA). Clinical samples from wound-healing patients and healthy controls were evaluated for AREG expression in CD4+ T cells by flow cytometry and qRT-PCR.

RESULTS

rmIL-33 treatment significantly enhanced Treg accumulation and AREG secretion in wound tissues, accelerating wound closure, collagen deposition, and re-epithelialization in wild-type mice. Areg deficiency markedly delayed healing, attenuated inflammatory cytokine regulation (TNF-α, TGF-β, IL-1β, IL-6), and reduced collagen synthesis (COL1, COL3). Recombinant TGF-β restored the wound-healing-promoting effects of Areg by reversing collagen metabolic disorders. Clinically, wound-healing patients showed increased AREG expression in skin tissues and Treg cells compared to controls.

CONCLUSION

IL-33 promotes wound healing by activating Tregs to secrete AREG, which in turn regulates tissue repair via the TGF-β signaling pathway. These findings highlight the IL-33/Treg/AREG/TGF-β axis as a potential therapeutic target for enhancing wound healing.