Purpose Giant cell arteritis (GCA) is a granulomatous vasculitis that preferentially targets medium-sized arteries, such as temporal arteries (TA), and causes blindness and aortic arch syndrome. Vessel wall injury is mediated by activated CD4 T cells and macrophages, with CD83+ dendritic cells (DCs) functioning as antigen-presenting cells. DCs are resident cells of the arterial wall. We have examined whether activation of vascular DCs is an early event in vasculitis and whether ligands for Toll-like receptors (TLR) induce vessel wall inflammation.
Methods Normal human TAs were kept in organ culture and stimulated with ligands specific for TLR4 and TLR5. Also, human TAs were implanted into SCID mice followed by TLR ligand injection and adoptive transfer of human CD4 T cells. The DC activation markers CD83 and CCL19 were assessed by real-time PCR and immunohistology. T-cell activation was quantified through CD40L and IFN-g transcripts. Proliferation of T cells isolated from the arteries was measured.
Results In the organ culture the TLR4 ligand LPS rapidly induced CD83 and CCL19 transcripts; immunohistochemistry revealed that CCL19 was produced by vascular DCs. Triggering of TLR5 by flagellin caused a different outcome; whereas CD83 was up-regulated to a similar extent, CCL19 production increased significantly more (p = .012). The biologic relevance of this difference for the induction of vascular inflammation was tested in the chimera model. LPS injection resulted in activation of vascular DCs and recruitment of adoptively transferred CD4+ T cells into the artery graft. T cells were activated, acquired a tissue-invasive phenotype and infiltrated the medial layer. Flagellin potently activated vascular DCs in vivo, inducing a CD83+ phenotype and the production of CCL19. Adoptively transferred T cells accumulated around differentiated DCs in the arterial adventitia. However, although T cells produced IFN-g they remained stationary and failed to invade the media.
Conclusions Temporal arteries possess a population of DCs that express TLR4 and TLR5 and respond to blood-born ligands of these receptors. Exposure to LPS results in retention of T cells, which differentiate into tissue-invasive effector cells typically seen in GCA. The bacterial product flagellin outperforms LPS in inducing T-cell recruitment to the vessel wall, yet such T cells are retained in the adventitia and do not imitate inflammatory infiltrates characteristic for GCA.
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