1 Department of Cariology, Restorative Sciences and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
2 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
J Dent Res. 2019 Jan;98(1):117-125. doi: 10.1177/0022034518796456. Epub 2018 Sep 6.
In the current concept of bacterial infections, pathogen-associated molecular patterns (PAMPs) derived from pathogens and damage-associated molecular patterns (DAMPs) released from damaged/necrotic host cells are crucial factors in induction of innate immune responses. However, the implication of DAMPs in apical and marginal periodontitis is unknown. Serum amyloid A (SAA) is a DAMP that is involved in the development of various chronic inflammatory diseases, such as rheumatoid arthritis. In the present study, we tested whether SAA is involved in the pathogenesis of periapical lesions, using human periapical surgical specimens and mice deficient in SAA and Toll-like receptors (TLR). SAA1/2 was locally expressed in human periapical lesions at the mRNA and protein levels. The level of SAA protein appeared to be positively associated with the inflammatory status of the lesions. In the development of mouse periapical inflammation, SAA1.1/2.1 was elevated locally and systemically in wild-type (WT) mice. Although SAA1.1/2.1 double-knockout and SAA3 knockout mice had redundant attenuation of the extent of periapical lesions, these animals showed strikingly improved inflammatory cell infiltration versus WT. Recombinant human SAA1 (rhSAA1) directly induced chemotaxis of WT neutrophils in a dose-dependent manner in vitro. In addition, rhSAA1 stimulation significantly prolonged the survival of WT neutrophils as compared with nonstimulated neutrophils. Furthermore, rhSAA1 activated the NF-κB pathway and subsequent IL-1α production in macrophages in a dose-dependent manner. However, TLR2/TLR4 double deficiency substantially diminished these SAA-mediated proinflammatory responses. Taken together, the SAA-TLR axis plays an important role in the chronicity of periapical inflammation via induction of inflammatory cell infiltration and prolonged cell survival. The interactions of PAMPs and DAMPs require further investigation in dental/oral inflammation.
在当前的细菌感染概念中，病原体相关分子模式（PAMPs）和受损/坏死宿主细胞释放的损伤相关分子模式（DAMPs）是诱导先天免疫反应的关键因素。然而，DAMPs 在根尖和边缘性牙周炎中的作用尚不清楚。血清淀粉样蛋白 A（SAA）是一种 DAMP，参与多种慢性炎症性疾病的发展，如类风湿关节炎。在本研究中，我们使用人根尖手术标本和 SAA 和 Toll 样受体（TLR）缺失的小鼠来检测 SAA 是否参与根尖病变的发病机制。SAA1/2 在人根尖病变中的 mRNA 和蛋白质水平上局部表达。SAA 蛋白水平似乎与病变的炎症状态呈正相关。在小鼠根尖炎症的发展过程中，野生型（WT）小鼠中 SAA1.1/2.1 局部和全身水平升高。尽管 SAA1.1/2.1 双敲除和 SAA3 敲除小鼠在根尖病变的严重程度上有明显减轻，但这些动物的炎症细胞浸润程度明显优于 WT。重组人 SAA1（rhSAA1）在体外以剂量依赖性方式直接诱导 WT 中性粒细胞的趋化性。此外，rhSAA1 刺激显著延长了 WT 中性粒细胞的存活时间，与未刺激的中性粒细胞相比。此外，rhSAA1 以剂量依赖性方式激活巨噬细胞中的 NF-κB 通路和随后的 IL-1α 产生。然而，TLR2/TLR4 双缺失大大减少了这些 SAA 介导的促炎反应。综上所述，SAA-TLR 轴通过诱导炎症细胞浸润和延长细胞存活时间，在根尖炎症的慢性化中发挥重要作用。PAMPs 和 DAMPs 的相互作用需要在口腔/牙科炎症中进一步研究。
