HIF-1α controls palatal wound healing by regulating macrophage motility via S1P/S1P₁ signaling axis

To investigate the role of hypoxia-inducible factor 1α (HIF-1α) signaling, the expression profile of M1 and M2 macrophages, and the role of the sphingosine 1-phosphate (S1P)/S1P receptor system in palatal wound healing of heterozygous HIF-1α-deficient (HIF-1α HET) mice.

HIF-1α HET and wild-type (WT) littermates underwent palatal tissue excision at the mid-hard palate. Histological analysis, immunostaining, real-time PCR, Western blotting (WB), and cellular migration assays were performed to analyze wound closure and macrophage infiltration.

DMOG pretreatment showed an acceleration of palatal wound closure in WT mice. In contrast, the delayed palatal wound closure was observed in HIF-1α HET mice with diminished production of Col1a1, MCP-1, and MIP-1α, compared with WT mice. Decreased infiltration of M1 macrophage (F4/80⁺ TNF-α⁺ , F4/80⁺ iNOS⁺ ) and M2 macrophage (F4/80⁺ Arginase-1⁺ , F4/80⁺ CD163⁺ ) was observed. The numbers of F4/80⁺ S1P₁ ⁺ macrophages of HIF-1α HET wounded tissues were significantly lower compared with WT tissues. S1P treatment of bone marrow macrophages (BMMs) significantly upregulated expression of S1P₁ in WT mice compared with HIF-1α HET. Phosphorylation of MAPK rapidly decreased in BMMs of HIF-1α HET mice than in BMMs of WT mice by S1P stimulation. Moreover, S1P enhanced HIF-1α expression via S1P₁ receptors to affect macrophage migration.

HIF-1α deficiency aggravates M1 and M2 macrophage infiltration and controls macrophage motility via S1P/S1P₁ signaling. These results suggest that HIF-1α signaling may contribute to the regulation of palatal wound healing.