Impaired phagosomal maturation in neutrophils leads to periodontitis in lysosomal-associated membrane protein-2 knockout mice
Impaired phagosomal maturation in neutrophils leads to periodontitis in lysosomal-associated membrane protein-2 knockout mice
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DOI：
10.4049/jimmunol.180.1.475
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发表时间：
2008-01-01
影响因子：
4.4
通讯作者：
Saftig, Paul
中科院分区：
文献类型：
--
作者：
Beertsen, Wouter;Willenborg, Marion;Saftig, Paul
炎症性牙周病是人类最常见的感染之一，导致牙列支撑结构的破坏。循环中性粒细胞是人体先天免疫系统的重要组成部分。我们观察到，缺乏主要溶酶体相关膜蛋白-2 （LAMP-2）的小鼠在生命早期会患上严重的牙周炎。这种发展伴随着沿牙齿表面细菌菌斑的大量积累、牙龈炎症、牙槽骨吸收、结缔组织纤维附着的丧失、连接上皮的根尖迁移和磨牙的病理性运动。炎性病变以多形核白细胞（pmn）为主，显然不能有效清除细菌病原体。用抗生素对lamp -2缺陷小鼠进行全身治疗，可预防牙周病变。从lamp -2缺陷小鼠中分离的PMNs显示自噬液泡的积累和细菌杀灭能力的降低。这些细胞的氧化爆发反应未发生改变。乳胶球和细菌喂养实验表明，吞噬体获得酸性pH值和晚期内吞标记物的能力降低，表明晚期内溶酶体与吞噬体的融合受损。这项研究强调了LAMP-2对PMNs吞噬体成熟的重要性。这也强调了溶酶体融合事件对PMNs提供足够的抗菌活性的要求，这是预防牙周病所需要的。
Inflammatory periodontal diseases constitute one of the most common infections in humans, resulting in the destruction of the supporting structures of the dentition. Circulating neutrophils are an essential component of the human innate immune system. We observed that mice deficient for the major lysosomal-associated membrane protein-2 (LAMP-2) developed severe periodontitis early in life. This development was accompanied by a massive accumulation of bacterial plaque along the tooth surfaces, gingival inflammation, alveolar bone resorption, loss of connective tissue fiber attachment, apical migration of junctional epithelium, and pathological movement of the molars. The inflammatory lesions were dominated by polymorphonuclear leukocytes (PMNs) apparently being unable to efficiently clear bacterial pathogens. Systemic treatment of LAMP-2-deficient mice with antibiotics prevented the periodontal pathology. Isolated PMNs from LAMP-2-deficient mice showed an accumulation of autophagic vacuoles and a reduced bacterial killing capacity. Oxidative burst response was not altered in these cells. Latex bead and bacterial feeding experiments showed a reduced ability of the phagosomes to acquire an acidic pH and late endocytic markers, suggesting an impaired fusion of late endosomes-lysosomes with phagosomes. This study underlines the importance of LAMP-2 for the maturation of phagosomes in PMNs. It also underscores the requirement of lysosomal fusion events to provide sufficient antimicrobial activity in PMNs, which is needed to prevent periodontal disease.