The inflammatory and immunogenic properties of the receptor for advanced glycation end products and its ligand, high mobility group box chromosomal protein 1

Abstract: Rheumatoid arthritis (RA) is a chronic systemic inflammatory joint disease, the pathogenesis of which is complex, involving a wide range of molecules. High mobility group box chromosomal protein 1 (HMGB1) is a nuclear protein recently recognised as a pro-inflammatory cytokine which levels are increased in RA patients. The interaction of HMGB1 with one of its receptors, receptor for advanced glycation end products (RAGE), leads to an inflammatory response. In contrast, the presence of soluble RAGE (sRAGE) has been suggested to function as a decoy by binding RAGE ligands and abrogating cellular activation. The aims of this thesis were to (I) investigate the role of HMGB1 in the development of arthritis; (II) to assess the properties of soluble RAGE in vivo as well as in vitro and to determine the role of sRAGE treatment in HMGB1 triggered arthritis; (III) to determine to what extent sRAGE is present in patients with RA, and to assess the association between sRAGE levels and disease characteristics; (IV) to investigate the immune response to sRAGE in RA patients. To evaluate the role of HMGB1 in arthritis, we administered recombinant HMGB1 into the knee joints of healthy mice. The results demonstrated that HMGB1 triggered joint inflammation. In vitro studies show that sRAGE in contrast to what was previously believed, exerts pro- rather than anti-inflammatory properties giving a dose-dependent rise to production of pro-inflammatory cytokines. Further, we demonstrated that this effect is at least partly triggered by interaction with Mac-1 and mediated via NF-ƒÛB pathway. Intra-peritoneal administration of sRAGE down regulated HMGB1-triggered arthritis, but the observed effect was due to a deviated inflammatory response from joint to peritoneal cavity. Finally, we demonstrated that sRAGE also acted as a chemotactic stimulus for neutrophils in vitro. Matching samples of blood and synovial fluid from RA patients were analysed regarding 1) sRAGE levels and 2) the immune response to sRAGE. RA patients displayed significantly decreased blood levels of sRAGE and higher blood and synovial fluid levels of anti-RAGE antibodies, as compared to healthy controls and patients with non-inflammatory joint disease. The presence of antibodies against sRAGE was associated with a more benign course of RA. Taken together, these results indicate that HMGB1 and sRAGE are pro-inflammatory molecules participating in the development of arthritis. The endogenous antibodies directed against sRAGE might neutralise the pro-inflammatory impact of this molecule, thereby affecting the clinical outcome of arthritis.