Toll-like receptors 4 and 5 induce distinct types of vasculitis.
Large vessel vasculitides, such as Takayasu arteritis and giant cell arteritis, affect vital arteries and cause clinical complications by either luminal occlusion or vessel wall destruction. Inflammatory infiltrates, often with granulomatous arrangements, are distributed as a panarteritis throughout all of the artery's wall layers or cluster in the adventitia as a perivasculitis. Factors determining the architecture and compartmentalization of vasculitis are unknown. Human macrovessels are populated by indigenous dendritic cells (DCs) positioned in the adventitia. Herein, we report that these vascular DCs sense bacterial pathogens and regulate the patterning of the emerging arteritis. In human temporal artery-SCID chimeras, lipopolysaccharides stimulating Toll-like receptor (TLR)4 and flagellin stimulating TLR5 trigger vascular DCs and induce T-cell recruitment and activation. However, the architecture of the evolving inflammation is ligand-specific; TLR4 ligands cause transmural panarteritis and TLR5 ligands promote adventitial perivasculitis. Underlying mechanisms involve selective recruitment of functional T cell subsets. Specifically, TLR4-mediated DC stimulation markedly enhances production of the chemokine CCL20, biasing recruitment toward CCL20-responsive CCR6(+) T cells. In adoptive transfer experiments, CCR6(+) T cells produce an arteritis pattern with media-invasive T cells damaging vascular smooth muscle cells. Also, CCR6(+) T cells dominate the vasculitic infiltrates in patients with panarteritic giant cell arteritis. Thus, depending on the original danger signal, vascular DCs edit the emerging immune response by differentially recruiting specialized T effector cells and direct the disease process toward distinct types of vasculitis.
Deng
Jiusheng
J
Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Ma-Krupa
Wei
W
Gewirtz
Andrew T
AT
Younge
Brian R
BR
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D013700:Giant Cell Arteritis / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000473:pathology; D054399:Receptors, CCR6 / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D013699:Temporal Arteries / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D046509:Tissue Culture Techniques; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000378:metabolism*
D000276:Adjuvants, Immunologic; C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D008024:Ligands; D054399:Receptors, CCR6; C495345:TLR4 protein, human; C495346:TLR5 protein, human; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5