Mitochondrial DNA-LL-37 Complex Promotes Atherosclerosis by Escaping from Autophagic Recognition.
Zhang. Zhiye Z; Meng. Ping P; Han. Yajun Y; Shen. Chuanbin C; Li. Bowen B; Hakim. Md Abdul MA; Zhang. Xuguang X; Lu. Qiumin Q; Rong. Mingqiang M; Lai. Ren R
Key Findings
- LL‑37‑mtDNA complexes are higher in blood and plaques of atherosclerotic subjects
- The complex resists DNase II degradation and escapes autophagic clearance
- It activates TLR9‑driven inflammation and worsens plaque formation in ApoE‑deficient mice
- Blocking the complex with antibodies lessens lesion development
Practical Outcomes
- For biohackers, the data suggest caution with any LL‑37‑boosting supplements or therapies, as they might promote heart‑related inflammation. Supporting autophagy (e.g., fasting, exercise, mTOR inhibitors) and monitoring inflammatory markers could help mitigate this risk, and future anti‑LL‑37 strategies may become a therapeutic avenue.
Summary
The study found that a natural immune molecule called LL‑37 can bind to leaked mitochondrial DNA, forming a complex that avoids the cell’s cleanup system and triggers inflammation that worsens artery plaque. In mice, this complex made atherosclerosis worse, while an antibody that blocks it reduced plaque buildup.
Abstract
Atherosclerosis is a chronic inflammatory disease of arterial wall. Mitochondrial DNA (mtDNA) and human antimicrobial peptide LL-37 (Cramp in mice) are involved in atherosclerosis. Recently, mtDNA has been found to escape from autophagy and cause inflammation. Normally, mtDNA as an inflammatogenic factor cannot escape from autophagy and degradation by DNase II. In this study, we found elevated amounts of LL37-mtDNA complex in atherosclerotic plasma and plaques. The complex was resistant to DNase II degradation and escaped from autophagic recognition, leading to activation of Toll-like receptor 9 (TLR9)-mediated inflammatory responses. Mouse model studies indicated that Cramp-mtDNA complex aggravated atherosclerotic lesion formation in apolipoprotein E-deficient mice and antibody treatment against the complex alleviated the lesion. These findings suggest that the LL-37-mtDNA complex acts as a key mediator of atherosclerosis formation, and thus represents a promising therapeutic target.
Study Information
pubmed
2015
2015-12-08T00:00:00.000Z
10.1016/j.immuni.2015.10.018
105
42