Amelogenin induces M2 macrophage polarisation via PGE2/cAMP signalling pathway

Kensuke Yamamichi, Takao Fukuda, Terukazu Sanui, Kyousuke Toyoda, Urara Tanaka, Yuki Nakao, Karen Yotsumoto, Hiroaki Yamato, Takaharu Taketomi, Takeshi Uchiumi, Fusanori Nishimura

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Objectives Amelogenin, the major component of the enamel matrix derivative (EMD), has been suggested as a bioactive candidate for periodontal regeneration. Apart from producing a regenerative effect on periodontal tissues, amelogenin has also been reported to have an anti-inflammatory effect. However, the precise molecular mechanisms underlying these effects remain unclear. In the present study, we examined the immunomodulatory effects of amelogenin on macrophages. Design Human phorbol 12-myristate 13-acetate (PMA)-differentiated U937 macrophages and CD14+ peripheral blood-derived monocytes (PBMC)-derived macrophages were stimulated with recombinant amelogenin (rM180). After performing a detailed microarray analysis, the effects of rM180 on macrophage phenotype and signal transduction pathways were evaluated by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, confocal microscopy and flow cytometry. Results The microarray analysis demonstrated that rM180 increased the expression of anti-inflammatory genes in lipopolysaccharide (LPS)-challenged macrophages after 24 h, while it temporarily up-regulated inflammatory responses at 4 h. rM180 significantly enhanced the expression of M2 macrophage markers (CD163 and CD206). rM180-induced M2 macrophage polarisation was associated with morphological changes as well as vascular endothelial growth factor (VEGF) production. rM180 enhanced prostaglandin E2 (PGE2) expression, and the activation of the cAMP/cAMP-responsive element binding (CREB) signaling pathway was involved in amelogenin-induced M2 macrophage polarisation. Blocking of PGE2 signaling by indomethacin specifically abrogated rM180 with or without LPS-induced M2 shift in PBMC-derived macrophages. Conclusion Amelogenin could reprogram macrophages into the anti-inflammatory M2 phenotype. It could therefore contribute to the early resolution of inflammation in periodontal lesions and provide a suitable environment for remodeling-periodontal tissues.

Original languageEnglish
Pages (from-to)241-251
Number of pages11
JournalArchives of Oral Biology
Volume83
DOIs
Publication statusPublished - Nov 1 2017

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Amelogenin
Dinoprostone
Macrophages
Anti-Inflammatory Agents
Microarray Analysis
Lipopolysaccharides
Phenotype
Dental Enamel
Confocal Microscopy
Indomethacin
Vascular Endothelial Growth Factor A
Real-Time Polymerase Chain Reaction
Regeneration
Signal Transduction
Flow Cytometry
Acetates
Enzyme-Linked Immunosorbent Assay

All Science Journal Classification (ASJC) codes

  • Otorhinolaryngology
  • Dentistry(all)
  • Cell Biology

Cite this

Amelogenin induces M2 macrophage polarisation via PGE2/cAMP signalling pathway. / Yamamichi, Kensuke; Fukuda, Takao; Sanui, Terukazu; Toyoda, Kyousuke; Tanaka, Urara; Nakao, Yuki; Yotsumoto, Karen; Yamato, Hiroaki; Taketomi, Takaharu; Uchiumi, Takeshi; Nishimura, Fusanori.

In: Archives of Oral Biology, Vol. 83, 01.11.2017, p. 241-251.

Research output: Contribution to journalArticle

Yamamichi, Kensuke ; Fukuda, Takao ; Sanui, Terukazu ; Toyoda, Kyousuke ; Tanaka, Urara ; Nakao, Yuki ; Yotsumoto, Karen ; Yamato, Hiroaki ; Taketomi, Takaharu ; Uchiumi, Takeshi ; Nishimura, Fusanori. / Amelogenin induces M2 macrophage polarisation via PGE2/cAMP signalling pathway. In: Archives of Oral Biology. 2017 ; Vol. 83. pp. 241-251.
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abstract = "Objectives Amelogenin, the major component of the enamel matrix derivative (EMD), has been suggested as a bioactive candidate for periodontal regeneration. Apart from producing a regenerative effect on periodontal tissues, amelogenin has also been reported to have an anti-inflammatory effect. However, the precise molecular mechanisms underlying these effects remain unclear. In the present study, we examined the immunomodulatory effects of amelogenin on macrophages. Design Human phorbol 12-myristate 13-acetate (PMA)-differentiated U937 macrophages and CD14+ peripheral blood-derived monocytes (PBMC)-derived macrophages were stimulated with recombinant amelogenin (rM180). After performing a detailed microarray analysis, the effects of rM180 on macrophage phenotype and signal transduction pathways were evaluated by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, confocal microscopy and flow cytometry. Results The microarray analysis demonstrated that rM180 increased the expression of anti-inflammatory genes in lipopolysaccharide (LPS)-challenged macrophages after 24 h, while it temporarily up-regulated inflammatory responses at 4 h. rM180 significantly enhanced the expression of M2 macrophage markers (CD163 and CD206). rM180-induced M2 macrophage polarisation was associated with morphological changes as well as vascular endothelial growth factor (VEGF) production. rM180 enhanced prostaglandin E2 (PGE2) expression, and the activation of the cAMP/cAMP-responsive element binding (CREB) signaling pathway was involved in amelogenin-induced M2 macrophage polarisation. Blocking of PGE2 signaling by indomethacin specifically abrogated rM180 with or without LPS-induced M2 shift in PBMC-derived macrophages. Conclusion Amelogenin could reprogram macrophages into the anti-inflammatory M2 phenotype. It could therefore contribute to the early resolution of inflammation in periodontal lesions and provide a suitable environment for remodeling-periodontal tissues.",
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AU - Yamamichi, Kensuke

AU - Fukuda, Takao

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AU - Tanaka, Urara

AU - Nakao, Yuki

AU - Yotsumoto, Karen

AU - Yamato, Hiroaki

AU - Taketomi, Takaharu

AU - Uchiumi, Takeshi

AU - Nishimura, Fusanori

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AB - Objectives Amelogenin, the major component of the enamel matrix derivative (EMD), has been suggested as a bioactive candidate for periodontal regeneration. Apart from producing a regenerative effect on periodontal tissues, amelogenin has also been reported to have an anti-inflammatory effect. However, the precise molecular mechanisms underlying these effects remain unclear. In the present study, we examined the immunomodulatory effects of amelogenin on macrophages. Design Human phorbol 12-myristate 13-acetate (PMA)-differentiated U937 macrophages and CD14+ peripheral blood-derived monocytes (PBMC)-derived macrophages were stimulated with recombinant amelogenin (rM180). After performing a detailed microarray analysis, the effects of rM180 on macrophage phenotype and signal transduction pathways were evaluated by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, confocal microscopy and flow cytometry. Results The microarray analysis demonstrated that rM180 increased the expression of anti-inflammatory genes in lipopolysaccharide (LPS)-challenged macrophages after 24 h, while it temporarily up-regulated inflammatory responses at 4 h. rM180 significantly enhanced the expression of M2 macrophage markers (CD163 and CD206). rM180-induced M2 macrophage polarisation was associated with morphological changes as well as vascular endothelial growth factor (VEGF) production. rM180 enhanced prostaglandin E2 (PGE2) expression, and the activation of the cAMP/cAMP-responsive element binding (CREB) signaling pathway was involved in amelogenin-induced M2 macrophage polarisation. Blocking of PGE2 signaling by indomethacin specifically abrogated rM180 with or without LPS-induced M2 shift in PBMC-derived macrophages. Conclusion Amelogenin could reprogram macrophages into the anti-inflammatory M2 phenotype. It could therefore contribute to the early resolution of inflammation in periodontal lesions and provide a suitable environment for remodeling-periodontal tissues.

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