title: Inhibition of Sprouty2 polarizes macrophages toward an M2 phenotype by stimulation with interferon γ and Porphyromonas gingivalis lipopolysaccharide.
abstract: Periodontitis is a chronic inflammatory disorder caused by specific bacteria residing in the biofilm, particularly Porphyromonas gingivalis (Pg). Sprouty2 (Spry2) functions as a negative regulator of the fibroblast growth factor (FGF) signaling pathway. We previously demonstrated that sequestration of Spry2 induced proliferation and osteogenesis in osteoblastic cells by basic FGF (bFGF) and epidermal growth factor (EGF) stimulation in vitro, but diminished cell proliferation in gingival epithelial cells. In addition, Spry2 knockdown in combination with bFGF and EGF stimulation increases periodontal ligament cell proliferation and migration accompanied by prevention of osteoblastic differentiation. In this study, we investigated the mechanisms through which Spry2 depletion by interferon (IFN) γ and Pg lipopolysaccharide (LPS) stimulation affected the physiology of macrophages in vitro. Transfection of macrophages with Spry2 small-interfering RNA (siRNA) promoted the expression of genes characteristic of M2 alternative activated macrophages, induced interleukin (IL)-10 expression, and enhanced arginase activity, even in cells stimulated with IFNγ and Pg LPS. In addition, we found that phosphoinositide 3-kinase (PI3K) and AKT activation by Spry2 downregulation enhanced efferocytosis of apoptotic cells by increasing Rac1 activation and decreasing nuclear factor kappa B (NFκB) p65 phosphorylation but not signal transducer and activator of transcription 1 (STAT1) phosphorylation. Collectively, our results suggested that topical administration of Spry2 inhibitors may efficiently resolve inflammation in periodontal disease as macrophage-based anti-inflammatory immunotherapy and may create a suitable environment for periodontal wound healing. These in vitro findings provide a molecular basis for new therapeutic approaches in periodontal tissue regeneration.
authors.affiliation: Division of Oral Rehabilitation Department of Periodontology Faculty of Dental Science Kyushu University Fukuoka Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Atomura
authors.affiliation: Division of Oral Rehabilitation Department of Periodontology Faculty of Dental Science Kyushu University Fukuoka Japan.
authors.forename: Terukazu
authors.initials: T
authors.lastname: Sanui
authors.affiliation: Division of Oral Rehabilitation Department of Periodontology Faculty of Dental Science Kyushu University Fukuoka Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Division of Oral Rehabilitation Department of Periodontology Faculty of Dental Science Kyushu University Fukuoka Japan.
authors.forename: Urara
authors.initials: U
authors.lastname: Tanaka
authors.affiliation: Division of Oral Rehabilitation Department of Periodontology Faculty of Dental Science Kyushu University Fukuoka Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Toyoda
authors.affiliation: Dental and Oral Medical Center Kurume University School of Medicine Fukuoka Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Taketomi
authors.affiliation: Division of Oral Rehabilitation Department of Periodontology Faculty of Dental Science Kyushu University Fukuoka Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Yamamichi
authors.affiliation: Division of Oral Rehabilitation Department of Periodontology Faculty of Dental Science Kyushu University Fukuoka Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Division of Oral Rehabilitation Department of Periodontology Faculty of Dental Science Kyushu University Fukuoka Japan.
authors.forename: Fusanori
authors.initials: F
authors.lastname: Nishimura
keywords: M2 macrophages; Porphyromonas gingivalis; Spry2; periodontal tissue regeneration