Inhibition of Sprouty2 polarizes macrophages toward an M2 phenotype by stimulation with interferon γ and Porphyromonas gingivalis lipopolysaccharide.
Inhibition of Sprouty2 polarizes macrophages toward an M2 phenotype by stimulation with interferon γ and Porphyromonas gingivalis lipopolysaccharide.
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DOI：
10.1002/iid3.99
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Nishimura F
中科院分区：
文献类型：
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作者：
Atomura R;Sanui T;Fukuda T;Tanaka U;Toyoda K;Taketomi T;Yamamichi K;Akiyama H;Nishimura F
牙周炎是由生物膜中的特定细菌，特别是牙龈卟啉单胞菌（Porphyromonas gingivalis，Pg）引起的慢性炎症性疾病。Sprouty 2（Spry 2）作为成纤维细胞生长因子（FGF）信号通路的负调节剂发挥作用。我们以前证明，隔离的Spry 2诱导增殖和成骨细胞的碱性成纤维细胞生长因子（bFGF）和表皮生长因子（EGF）的体外刺激，但减少牙龈上皮细胞的细胞增殖。此外，Spry 2敲除与bFGF和EGF刺激组合增加牙周韧带细胞增殖和迁移，伴随着成骨细胞分化的预防。在这项研究中，我们研究了干扰素（IFN）γ和Pg脂多糖（LPS）刺激的Spry 2耗竭影响体外巨噬细胞生理学的机制。用Spry 2小干扰RNA（siRNA）转染巨噬细胞可促进M2交替活化巨噬细胞特征性基因的表达，诱导白细胞介素（IL）-10表达，并增强巨噬细胞吞噬酶活性，即使在用IFNγ和Pg LPS刺激的细胞中也是如此。此外，我们发现磷酸肌醇3-激酶（PI 3 K）和AKT通过Spry 2下调激活通过增加Rac 1激活和减少核因子κ B（NFκB）p65磷酸化而不是信号转导和转录激活因子1（STAT 1）磷酸化来增强凋亡细胞的凋亡细胞。总的来说，我们的研究结果表明，局部施用Spry 2抑制剂可以有效地解决牙周病炎症，作为基于巨噬细胞的抗炎免疫疗法，并可以为牙周伤口愈合创造合适的环境。这些体外研究结果为牙周组织再生的新治疗方法提供了分子基础。
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.