Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils.
Porphyromonas gingivalis gingipains cause defective macrophage migration towards apoptotic cells and inhibit phagocytosis of primary apoptotic neutrophils.
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DOI：
10.1038/cddis.2016.481
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发表时间：
2017-03-02
影响因子：
9
通讯作者：
Devitt A
中科院分区：
文献类型：
--
作者：
Castro SA;Collighan R;Lambert PA;Dias IH;Chauhan P;Bland CE;Milic I;Milward MR;Cooper PR;Devitt A
牙周病是一种流行的慢性炎症性疾病，其特征在于宿主对致病菌斑生物膜的异常反应，导致局部组织损伤和愈合受阻，从而导致牙齿脱落。来自关键牙周病原体牙龈卟啉单胞菌的半胱氨酸蛋白酶（牙龈菌蛋白酶）通过抑制炎症消退而与牙周病发病机制有关，并且与全身性慢性炎症性病症如类风湿性关节炎有关。凋亡细胞的有效清除对于炎症的解决和组织修复是必不可少的。在这里，我们试图阐明凋亡细胞的先天免疫清除及其由牙龈卟啉菌蛋白酶的调节。我们研究了牙龈卟啉菌蛋白酶处理的巨噬细胞迁移和吞噬凋亡细胞的能力。赖氨酸牙龈卟啉菌蛋白酶处理巨噬细胞损害巨噬细胞向凋亡中性粒细胞的迁移。此外，赖氨酸牙龈卟啉菌蛋白酶处理降低了凋亡细胞的关键巨噬细胞受体CD 14的表面表达水平，这导致巨噬细胞与凋亡细胞的相互作用减少。此外，虽然凋亡细胞及其衍生的分泌组被证明可以抑制牙龈卟啉单胞菌脂多糖诱导的TNF-α表达，但我们证明牙龈蛋白酶制剂在巨噬细胞中诱导了快速的炎症反应，而巨噬细胞对凋亡细胞或其分泌组的抗炎作用具有抵抗力。总之，这些数据表明牙龈卟啉单胞菌可能通过多种机制促进牙周病患者中观察到的慢性炎症，包括快速、有效的牙龈卟啉菌蛋白酶介导的炎症，加上受体裂解导致凋亡细胞的清除缺陷和抗炎反应降低。因此，牙龈卟啉菌蛋白酶代表了一个潜在的治疗目标，在慢性牙周病的管理干预。
Periodontal disease is a prevalent chronic inflammatory condition characterised by an aberrant host response to a pathogenic plaque biofilm resulting in local tissue damage and frustrated healing that can result in tooth loss. Cysteine proteases (gingipains) from the key periodontal pathogen Porphyromonas gingivalis have been implicated in periodontal disease pathogenesis by inhibiting inflammation resolution and are linked with systemic chronic inflammatory conditions such as rheumatoid arthritis. Efficient clearance of apoptotic cells is essential for the resolution of inflammation and tissue restoration. Here we sought to characterise the innate immune clearance of apoptotic cells and its modulation by gingipains. We examined the capacity of gingipain-treated macrophages to migrate towards and phagocytose apoptotic cells. Lysine gingipain treatment of macrophages impaired macrophage migration towards apoptotic neutrophils. Furthermore, lysine gingipain treatment reduced surface expression levels of CD14, a key macrophage receptor for apoptotic cells, which resulted in reduced macrophage interactions with apoptotic cells. Additionally, while apoptotic cells and their derived secretome were shown to inhibit TNF-α-induced expression by P. gingivalis lipopolysaccharide, we demonstrated that gingipain preparations induced a rapid inflammatory response in macrophages that was resistant to the anti-inflammatory effects of apoptotic cells or their secretome. Taken together, these data indicate that P. gingivalis may promote the chronic inflammation seen in periodontal disease patients by multiple mechanisms, including rapid, potent gingipain-mediated inflammation, coupled with receptor cleavage leading to defective clearance of apoptotic cells and reduced anti-inflammatory responses. Thus, gingipains represent a potential therapeutic target for intervention in the management of chronic periodontal disease.