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

Objectives: 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.

Materials And Methods: 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.

Results: 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 S1P 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 S1P 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 S1P receptors to affect macrophage migration.

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