Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
Division of Pulmonary, Critical Care & Sleep Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
FASEB J. 2024 Dec;38(23):e70214. doi: 10.1096/fj.202401571RR.
Extracellular histones are released in two major forms: free histones and nucleosomes (DNA-bound histones). However, little distinction has been made between these two forms of circulating extracellular histones. Our study detected increased circulating nucleosomes in acute lung injury patients. Further, our group identified nucleosomes as the leading form of extracellular histones compared to free histones in the plasma of COVID-19 patients, underscoring the necessity to reassess the forms of circulating histones and nucleosome contributions to immunopathology. Functionally, nucleosomes activated macrophages and induced inflammation in different organs. Mechanistically, we observed nucleosomes activating the NF-κB signaling, while inhibition of NF-κB by sulfasalazine attenuated nucleosome-induced macrophage activation. Taken together, our study indicates that extracellular histones are predominantly released as nucleosomes, playing a critical role in the inflammation of the lungs and other organs.
游离组蛋白和核小体（与 DNA 结合的组蛋白）。然而，人们很少区分这两种循环细胞外组蛋白形式。我们的研究在急性肺损伤患者中检测到循环核小体增加。此外，我们的研究小组发现，与 COVID-19 患者血浆中的游离组蛋白相比，核小体是细胞外组蛋白的主要形式，这强调了有必要重新评估循环组蛋白的形式和核小体对免疫病理学的贡献。从功能上讲，核小体激活了巨噬细胞，并在不同的器官中引发炎症。从机制上讲，我们观察到核小体激活 NF-κB 信号通路，而柳氮磺胺吡啶抑制 NF-κB 可减弱核小体诱导的巨噬细胞激活。总之，我们的研究表明，细胞外组蛋白主要以核小体的形式释放，在肺部和其他器官的炎症中发挥关键作用。
