Fibroblast-derived alarmin promotes oral wound healing by activating Tregs that relay pro_x0002_angiogenic and anti-inflammatory

ABSTRACT: Fibroblasts are abundant structural cells that produce extracellular matrix components and are essential for tissue repair following an injury. Emerging evidence highlights a crucial immunomodulatory role of fibroblasts in health and disease, which is incompletely explored in the wound healing field. Here, we used an oral wound healing model that heals exceptionally fast with minimal scarring and investigated if select fibroblasts are endowed with immune-regulatory functions that can have an impact on optimal healing outcomes. We identified PI16+ oral reticular fibroblasts to be highly enriched in interleukin-33 (IL33), an alarmin cytokine that is rapidly released during the early stages of wound healing. Using mice with lineage-specific, inducible deletion of IL33, we found that baseline expression of IL33 from fibroblasts but not keratinocytes was necessary for proper wound healing in oral mucosa. Singe cell RNA-sequencing (scRNA-seq)analysis revealed that regulatory T cells (Tregs) respond to IL33 and upregulate the expression of a pro-inflammatory cytokine MIF and an anti-inflammatory cytokine TGFB1, which was validated in vivo. Mechanistically, MIF promotes recruitment of angiogenic monocytes to facilitate blood vessel formation in healing wounds, whereas TGFB1 supports an early transition of macrophages to a pro-resolving phenotype. Importantly, we show that human oral mucosa, but not skin, harbors IL33+ PI16+ reticular fibroblasts in deeper aspects of the connective tissue and that Tregs express MIF and TGFB1 in regenerating oral mucosa. Together, our study unveils an essential role of IL33+ oral reticular fibroblasts for the modulation of acute inflammation by engaging Tregs that promote angiogenesis and resolution of inflammation in wound healing.

ORGANISM(S): Mus musculus

PROVIDER: GSE292645 | GEO | 2026/01/08

REPOSITORIES: GEO