Toll-Like Receptor 7 Protects from Atherosclerosis by Constraining 'Inflammatory' Macrophage Activation
Background—Toll-like receptors (TLRs) have long been considered to be major culprits for the development of atherosclerosis, contributing both to its progression and clinical complications. However, evidence for most TLRs beyond TLR2 and TLR4 is lacking.
Methods and Results—We used experimental mouse models, human atheroma cultures and well established human biobanks to investigate the role of TLR7 in atherosclerosis. We report the unexpected finding that TLR7, a receptor recognizing self nucleic acid complexes, is protective in atherosclerosis. In Apoe-/- mice, functional inactivation of TLR7 resulted in accelerated lesion development, increased stenosis and enhanced plaque vulnerability as revealed by doppler ultrasound and/or histopathology. Mechanistically, TLR7 interfered with macrophage pro-inflammatory responses to TLR2 and TLR4 ligands, reduced MCP-1 production, and prevented expansion of Ly6Chi 'inflammatory' monocytes and accumulation of 'inflammatory' M1 macrophages into developing atherosclerotic lesions. Consistently, in human carotid endarterectomy specimens TLR7 levels were associated with an M2 anti-inflammatory macrophage signature (IL-10, IL-1RA, CD163, scavenger and C-type lectin receptors) and collagen genes, while they were inversely related or unrelated to pro-inflammatory mediators (IL-12/IL-23, IFNβ, IFNγ, CD40L) and platelet markers. Moreover, in human atheroma cultures TLR7 activation selectively suppressed the production of key pro-atherogenic factors such as MCP-1 and TNF without affecting IL-10.
Conclusions—These findings provide evidence for a beneficial role of TLR7 in atherosclerosis by constraining 'inflammatory' macrophage activation and cytokine production. This challenges the prevailing concept that all TLRs are pathogenic, and supports the exploitation of the TLR7 pathway for therapy.
- Received September 14, 2011.
- Accepted June 22, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited