2024-03-21 デューク大学(Duke)
◆デューク大学の研究チームは、特定のサイズの微粒子にDNAを結合させ、免疫細胞との相互作用を試験する方法を開発しました。この研究は、免疫細胞がDNA-微粒子複合体に反応し、炎症シグナルを発することを示しました。
<関連情報>
- https://pratt.duke.edu/news/auto-immune-nanoparticle-platform/
- https://www.pnas.org/doi/10.1073/pnas.2319634121
ナノ粒子に付着したDNAコロナが免疫刺激効果を増強し、自己免疫疾患への示唆をもたらす DNA corona on nanoparticles leads to an enhanced immunostimulatory effect with implications for autoimmune diseases
Faisal Anees, Diego A. Montoya, David S. Pisetsky, and Christine K. Payne
Proceedings of the National Academy of Sciences Published:March 5, 2024
DOI:https://doi.org/10.1073/pnas.2319634121
Significance
A mechanistic understanding of many autoimmune and inflammatory diseases is currently lacking. Recent work has shown that cell-free DNA bound to biological microparticles is linked to systemic lupus erythematosus and related conditions. However, the heterogeneity and technical challenges associated with biological particles have hindered a mechanistic understanding of their role in this disease. We have created a model system of DNA–particles and used these particles to understand the cellular response to DNA–particle complexes. These findings are important for considering inflammation in response to DNA on particle surfaces and providing a model system for further study of the role of particles in immune-mediated disease.
Abstract
Autoimmune and inflammatory diseases are highly complex, limiting treatment and the development of new therapies. Recent work has shown that cell-free DNA bound to biological microparticles is linked to systemic lupus erythematosus, a prototypic autoimmune disease. However, the heterogeneity and technical challenges associated with the study of biological particles have hindered a mechanistic understanding of their role. Our goal was to develop a well-controlled DNA–particle model system to understand how DNA–particle complexes affect cells. We first characterized the adsorption of DNA on the surface of polystyrene nanoparticles (200 nm and 2 µm) using transmission electron microscopy, dynamic light scattering, and colorimetric DNA concentration assays. We found that DNA adsorbed on the surface of nanoparticles was resistant to degradation by DNase 1. Macrophage cells incubated with the DNA–nanoparticle complexes had increased production of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). We probed two intracellular DNA sensing pathways, toll-like receptor 9 (TLR9) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), to determine how cells sense the DNA–nanoparticle complexes. We found that the cGAS-STING pathway is the primary route for the interaction between DNA–nanoparticles and macrophages. These studies provide a molecular and cellular-level understanding of DNA–nanoparticle–macrophage interactions. In addition, this work provides the mechanistic information necessary for future in vivo experiments to elucidate the role of DNA–particle interactions in autoimmune diseases, providing a unique experimental framework to develop novel therapeutic approaches.
