start-ver=1.4 cd-journal=joma no-vol=22 cd-vols= no-issue=16 article-no= start-page=8992 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210820 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Macrophage Motility in Wound Healing Is Regulated by HIF-1 alpha via S1P Signaling en-subtitle= kn-subtitle= en-abstract= kn-abstract=Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1 alpha is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1 alpha regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1 alpha have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1 alpha/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1 alpha is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing. en-copyright= kn-copyright= en-aut-name=HutamiIslamy Rahma en-aut-sei=Hutami en-aut-mei=Islamy Rahma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IzawaTakashi en-aut-sei=Izawa en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Khurel-OchirTsendsuren en-aut-sei=Khurel-Ochir en-aut-mei=Tsendsuren kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakamakiTakuma en-aut-sei=Sakamaki en-aut-mei=Takuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IwasaAkihiko en-aut-sei=Iwasa en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TanakaEiji en-aut-sei=Tanaka en-aut-mei=Eiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School kn-affil= affil-num=2 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School kn-affil= affil-num=4 en-affil=Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School kn-affil= affil-num=5 en-affil=Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School kn-affil= affil-num=6 en-affil=Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School kn-affil= en-keyword=HIF1 kn-keyword=HIF1 en-keyword=M1/M2 macrophage kn-keyword=M1/M2 macrophage en-keyword=S1P kn-keyword=S1P en-keyword=wound healing kn-keyword=wound healing END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue=1 article-no= start-page=14927 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210721 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Roles for B[a]P and FICZ in subchondral bone metabolism and experimental temporomandibular joint osteoarthritis via the AhR/Cyp1a1 signaling axis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Bone loss due to smoking represents a major risk factor for fractures and bone osteoporosis. Signaling through the aryl hydrocarbon receptor (AhR) and its ligands contributes to both bone homeostasis and inflammatory diseases. It remains unclear whether the same AhR signaling axis affects the temporomandibular joint (TMJ). The aim of this study was to investigate possible mechanisms which mediate bone loss in the TMJ due to smoking. In particular, whether benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke, induces expression of the AhR target gene, Cyp1a1, in mandibular condyles. Possible functions of an endogenous ligand of FICZ, were also investigated in a TMJ-osteoarthritis (OA) mouse model. B[a]P was administered orally to wild-type and AhR(-/-) mice and bone metabolism was subsequently examined. TMJ-OA was induced in wild-type mice with forceful opening of the mouth. Therapeutic functions of FICZ were detected with mu CT and histology. Exposure to B[a]P accelerated bone loss in the mandibular subchondral bone. This bone loss manifested with osteoclastic bone resorption and upregulated expression of Cyp1a1 in an AhR-dependent manner. In a mouse model of TMJ-OA, FICZ exhibited a dose-dependent rescue of mandibular subchondral bone loss by repressing osteoclast activity. Meanwhile, in vitro, pre-treatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[a]P regulates mandibular subchondral bone metabolism via the Cyp1a1. The AhR ligand, FICZ, can prevent TMJ-OA by regulating osteoclast differentiation. en-copyright= kn-copyright= en-aut-name=YoshikawaYuri en-aut-sei=Yoshikawa en-aut-mei=Yuri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IzawaTakashi en-aut-sei=Izawa en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HamadaYusaku en-aut-sei=Hamada en-aut-mei=Yusaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakenagaHiroko en-aut-sei=Takenaga en-aut-mei=Hiroko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IshimaruNaozumi en-aut-sei=Ishimaru en-aut-mei=Naozumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KamiokaHiroshi en-aut-sei=Kamioka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences kn-affil= affil-num=7 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=28 cd-vols= no-issue=4 article-no= start-page=1157 end-page=1169 dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20214 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=HIF-1 alpha controls palatal wound healing by regulating macrophage motility via S1P/S1P(1) signaling axis kn-title=HIF]1 controls palatal wound healing by regulating macrophage motility via S1P/S1P1 signaling axis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objectives
To investigate the role of hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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-1 alpha-deficient (HIF-1 alpha HET) mice. Materials and methods HIF-1 alpha 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-1 alpha HET mice with diminished production of Col1a1, MCP-1, and MIP-1 alpha, compared with WT mice. Decreased infiltration of M1 macrophage (F4/80(+)TNF-alpha(+), F4/80(+)iNOS(+)) and M2 macrophage (F4/80(+)Arginase-1(+), F4/80(+)CD163(+)) was observed. The numbers of F4/80(+)S1P(1)(+) macrophages of HIF-1 alpha HET wounded tissues were significantly lower compared with WT tissues. S1P treatment of bone marrow macrophages (BMMs) significantly upregulated expression of S1P(1) in WT mice compared with HIF-1 alpha HET. Phosphorylation of MAPK rapidly decreased in BMMs of HIF-1 alpha HET mice than in BMMs of WT mice by S1P stimulation. Moreover, S1P enhanced HIF-1 alpha expression via S1P(1) receptors to affect macrophage migration.

Conclusions
HIF-1 alpha deficiency aggravates M1 and M2 macrophage infiltration and controls macrophage motility via S1P/S1P(1) signaling. These results suggest that HIF-1 alpha signaling may contribute to the regulation of palatal wound healing. en-copyright= kn-copyright= en-aut-name=HutamiIslamy Rahma en-aut-sei=Hutami en-aut-mei=Islamy Rahma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IzawaTakashi en-aut-sei=Izawa en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Khurel]OchirTsendsuren en-aut-sei=Khurel]Ochir en-aut-mei=Tsendsuren kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakamakiTakuma en-aut-sei=Sakamaki en-aut-mei=Takuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IwasaAkihiko en-aut-sei=Iwasa en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TomitaShuhei en-aut-sei=Tomita en-aut-mei=Shuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TanakaEiji en-aut-sei=Tanaka en-aut-mei=Eiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan kn-affil= affil-num=2 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan kn-affil= affil-num=4 en-affil=Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan kn-affil= affil-num=5 en-affil=Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan kn-affil= affil-num=6 en-affil=Department of Pharmacology Osaka City University Graduate School of Medicine Osaka Japan kn-affil= affil-num=7 en-affil=Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan kn-affil= en-keyword=HIF-1 kn-keyword=HIF-1 en-keyword=S1P receptor kn-keyword=S1P receptor en-keyword=hypoxia kn-keyword=hypoxia en-keyword=wound healing kn-keyword=wound healing en-keyword=M1/M2 macrophage kn-keyword=M1/M2 macrophage en-keyword=DMOG kn-keyword=DMOG END