HIF-1α controls palatal wound healing by regulating macrophage motility via S1P/S1P1 signaling axis
Tanaka E., Izawa T., Iwasa A., Hutami I.R., Sakamaki T., Khurel-Ochir T., Tomita S.
Abstract
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<sup>+</sup>TNF-α<sup>+</sup>, F4/80<sup>+</sup>iNOS<sup>+</sup>) and M2 macrophage (F4/80<sup>+</sup>Arginase-1<sup>+</sup>, F4/80<sup>+</sup>CD163<sup>+</sup>) was observed. The numbers of F4/80<sup>+</sup>S1P<inf>1</inf><sup>+</sup> 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<inf>1</inf> 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<inf>1</inf> receptors to affect macrophage migration. Conclusions: HIF-1α deficiency aggravates M1 and M2 macrophage infiltration and controls macrophage motility via S1P/S1P<inf>1</inf> signaling. These results suggest that HIF-1α signaling may contribute to the regulation of palatal wound healing.
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Cell Communication and Signaling
