Huang Max Tze-Han, Taxman Debra J, Holley-Guthrie Elizabeth A, Moore Chris B, Willingham Stephen B, Madden Victoria, Parsons Rebecca Keyser, Featherstone Gerald L, Arnold Roland R, O'Connor Brian P, Ting Jenny Pan-Yun
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
J Immunol. 2009 Feb 15;182(4):2395-404. doi: 10.4049/jimmunol.0800909.
Periodontal disease is a chronic inflammatory disorder that leads to the destruction of tooth-supporting tissue and affects 10-20 million people in the U.S. alone. The oral pathogen Porphyromonas gingivalis causes inflammatory host response leading to periodontal and other secondary inflammatory diseases. To identify molecular components that control host response to P. gingivalis in humans, roles for the NLR (NBD-LRR) protein, NLRP3 (cryopyrin, NALP3), and its adaptor apoptotic speck protein containing a C-terminal caspase recruitment domain (ASC) were studied. P. gingivalis strain A7436 induces cell death in THP1 monocytic cells and in human primary peripheral blood macrophages. This process is ASC and NLRP3 dependent and can be replicated by P. gingivalis LPS and Escherichia coli. P. gingivalis-induced cell death is caspase and IL-1 independent and exhibits morphological features consistent with necrosis including loss of membrane integrity and release of cellular content. Intriguingly, P. gingivalis-induced cell death is accompanied by the formation of ASC aggregation specks, a process not previously described during microbial infection. ASC specks are observed in P. gingivalis-infected primary human mononuclear cells and are dependent on NLRP3. This work shows that P. gingivalis causes ASC- and NLRP3-dependent necrosis, accompanied by ASC speck formation.
牙周病是一种慢性炎症性疾病，可导致牙齿支持组织的破坏，仅在美国就影响1000万至2000万人。口腔病原体牙龈卟啉单胞菌可引起宿主炎症反应，导致牙周炎和其他继发性炎症性疾病。为了确定控制人类对牙龈卟啉单胞菌宿主反应的分子成分，研究了NLR（NBD-LRR）蛋白、NLRP3（冷吡啉、NALP3）及其含有C末端半胱天冬酶募集结构域（ASC）的衔接蛋白凋亡斑点蛋白的作用。牙龈卟啉单胞菌A7436菌株可诱导THP1单核细胞和人原代外周血巨噬细胞死亡。这一过程依赖于ASC和NLRP3，牙龈卟啉单胞菌脂多糖和大肠杆菌也可复制这一过程。牙龈卟啉单胞菌诱导的细胞死亡不依赖于半胱天冬酶和白细胞介素-1，表现出与坏死一致的形态学特征，包括膜完整性丧失和细胞内容物释放。有趣的是，牙龈卟啉单胞菌诱导的细胞死亡伴随着ASC聚集斑点的形成，这一过程在微生物感染中以前没有描述过。在牙龈卟啉单胞菌感染的原代人单核细胞中观察到ASC斑点，且依赖于NLRP3。这项研究表明，牙龈卟啉单胞菌可导致ASC和NLRP3依赖性坏死，并伴有ASC斑点形成。
