Early recruitment of phagocytes contributes to the vascular inflammation of giant cell arteritis

Abstract

Vascular inflammation in giant cell arteritis is generally described as a process involving dendritic cells, T-lymphocytes, and effector tissue macrophages. Less is known about the contribution of phagocytes that are recruited early, such as monocytes and neutrophils. These cells express and secrete pro-inflammatory S100 proteins which directly activate endothelial cells. In this study the expression of S100A8/S100A9 and S100A12, pro-inflammatory proteins specific for early recruited phagocytes, was studied in biopsies from 36 patients with giant cell arteritis. In addition, serum concentrations of these proteins were analysed in serum samples from 42 patients and 35 healthy controls. The S100A8/S100A9 complex was found to be abundant in the adventitia and media in affected arteries. Besides neutrophils, cells expressing these proteins belonged to a pro-inflammatory subtype of CD68-positive monocytes. In contrast, S100A12 expression was restricted to neutrophils that were found around the vasa vasorum within the adventitial layer. Both S100A8/S100A9 and S100A12 serum concentrations were significantly higher in patients with giant cell arteritis than in healthy controls. In conclusion, recently recruited phagocytes expressing pro-inflammatory S100 proteins take part in the vascular inflammation of giant cell arteritis. They may play important roles at the vasa vasorum of affected vessels, which represent sites of entry for recruited inflammatory cells. These data indicate that phagocytes within the adventitia and media contribute to the process of inflammation via release of the pro-inflammatory S100 proteins S100A8, S100A9, and S100A12.

Acute Kawasaki disease is associated with reverse regulation of soluble receptor for advance glycation end products and its proinflammatory ligand S100A12

“…S100A12 exerts its proinflammatory effects on endothelium and leukocytes via binding to RAGE expressed on these cells (8,9). It is feasible that the exaggerated release of this S100 protein at sites of vascular inflammation induces a positive feedback loop in which primed phagocytes and S100A12-stimulated endothelium facilitate the further recruitment of even more leukocytes (1,10,27,28,31,33). Blockade of S100A12 activity with sRAGE attenuated inflammation and inhibited the up-regulation of cytokines and transcription factors such as NF-B in vitro as well as in murine models of inflammation (4,5).…”

“…Thus, changing concentrations of the proinflammatory ligand may be of greater biologic relevance than changes in sRAGE levels, as confirmed by the S100A12 levels in the most severely affected patients with systemic-onset JIA. S100A12 is secreted from activated neutrophils, the level of which is markedly elevated in KD, and activated neutrophils play a major role in vasculitic tissue damage (1,10,27,28,31,33). S100A12 exerts its proinflammatory effects on endothelium and leukocytes via binding to RAGE expressed on these cells (8,9).…”

“…Subsequently, the polyhistidine-tag amino acid motif was cleaved from the protein by thrombin cleavage and capture (Novagen, Madison WI). Specific polyclonal affinity-purified rabbit antibodies against human S100A12 were prepared as described previously (27,28). Recombinant human sRAGE (aa 22-342 of the protein) was generated from stably transfected HeLa cell clones and purified as previously reported (29).…”

New insights into the pathogenesis of giant cell arteritis

“…Abundant neutrophils are present in the vasa vasorum and small vessels around temporal arteries in GCA [12,95] suggesting their involvement in GCA pathogenesis. Recently, the role of neutrophils in GCA pathogenesis has been studied by Nadkarni S et al [96].…”

Chronic Inflammation and S100A12/ Receptor for Advanced Glycation Endproducts Axis: A Novel Risk Factor for Cardiovascular Disease in Patients with Chronic Kidney Disease?

“…Each monomer is composed of a C-terminal, classic EF-hand, common to all EF-hand proteins, and an N-terminal, pseudo EF-hand, which has been found exclusively in the N-termini of S100 and S100-like proteins (Pietzsch and Hoppmann, 2009;Zhou et al, 2006). In recent years, a subgroup of the S100 family (S100A12, S100A8, and S100A9) has been associated with acute/chronic inflammatory disorders (Foell et al, 2004a;Foell et al, 2004b). Human S100A12 was first described by Guignard and colleagues as a cytosolic protein, p6, in neutrophilic granulocytes and monocytes/macrophages that crossreacts with antibodies raised against S100A8 (Guignard et al, 1995).…”