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 in the development of atherosclerosis, contributing both to its progression and clinical complications. However, evidence for most TLRs beyond TLR2 and TLR4 is lacking.


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 proinflammatory responses to TLR2 and TLR4 ligands, reduced monocyte chemoattractant protein-1 production, and prevented expansion of Ly6C(hi) inflammatory monocytes and accumulation of inflammatory M1 macrophages into developing atherosclerotic lesions. In human carotid endarterectomy specimens TLR7 levels were consistently associated with an M2 anti-inflammatory macrophage signature (interleukin [IL]-10, IL-1RA, CD163, scavenger and C-type lectin receptors) and collagen genes, whereas they were inversely related or unrelated to proinflammatory mediators (IL-12/IL-23, interferon beta, interferon gamma, CD40L) and platelet markers. Moreover, in human atheroma cultures, TLR7 activation selectively suppressed the production of key proatherogenic factors such as monocyte chemoattractant protein-1 and tumor necrosis factor 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.
Center for Immunology and Transplantation, Biomedical Research Foundation, Academy of Athens, Soranou Efesiou 4, Athens 11527, Greece.
Maria
M
Salagianni
Ioanna E
IE
Galani
Anna M
AM
Lundberg
Constantinos H
CH
Davos
Aimilia
A
Varela
Ariana
A
Gavriil
Leo-Pekka
LP
Lyytikäinen
Terho
T
Lehtimäki
Fragiska
F
Sigala
Lasse
L
Folkersen
Vassilis
V
Gorgoulis
Sébastien
S
Lenglet
Fabrizio
F
Montecucco
François
F
Mach
Ulf
U
Hedin
Göran K
GK
Hansson
Claudia
C
Monaco
Evangelos
E
Andreakos
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology*
D001057:Apolipoproteins E; D015415:Biomarkers; D016207:Cytokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C495348:TLR7 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7