Alarmins of the S100-Family in Juvenile Autoimmune and Auto-Inflammatory Diseases

Abstract

Autoimmune and auto-inflammatory diseases in children are causing chronic inflammation, organ damage, and pain. Although several options for treatment are nowadays available a significant number of patients does not respond sufficiently to current therapies. In these diseases inflammatory processes are triggered by numerous exogenous and endogenous factors. There is now increasing evidence that especially a novel family of pro-inflammatory molecules, named alarmins, play a significant role in inflammatory processes underlying these diseases. Alarmins are endogenous proteins released during stress reactions that confer inflammatory signaling via Pattern Recognition Receptors (PRRs), like the Toll-like receptor 4 (TLR4). The most abundant alarmins in juvenile rheumatic diseases belong to the family of pro-inflammatory calcium-binding S100-proteins. In this review we will give a general introduction in S100-biology. We will demonstrate the functional relevance of these proteins in animal models of autoimmune and auto-inflammatory diseases. We will show the expression patterns of S100-alarmins and correlation to disease activity in different forms of juvenile idiopathic arthritis, auto-inflammatory diseases, and systemic autoimmune disorders. Finally, we will discuss the clinical use of S100-alarmins as biomarkers for diagnosis and monitoring of rheumatic diseases in children and will point out potential future therapeutic approaches targeting inflammatory effects mediated by S100-alarmins.

Keywords: DAMP; S100; alarmins; autoinflammation; biomarker; rheumatic diseases.

Figure 1

Pathogen associated molecular pattern molecules (PAMPs) are released by bacterial pathogens during infections (1). Accordingly, tissue stress or cellular activation may lead to release of endogenous alarmins or danger associated molecular pattern molecules (DAMPs) under sterile conditions (2). PAMPs and alarmins/DAMPs bind to and activate specific pattern recognition receptors on effector cells (3), which promote inflammatory processes.

Figure 2

Various inflammatory triggers lead to local release of S100A8/S100A9 dimers by activated monocytes or granulocytes (1). S100A8/S100A9 may bind to TLR4 on different target cells and amplify and perpetuate the inflammatory response (2). With increasing calcium concentrations toward systemic circulation S100A8/S100A9 dimers bind calcium ions (3) and form (S100A8/S100A9)₂ tetramers (4) which show no inflammatory activity any more due to the fact that the TLR4 binding site is hidden in the tetramer interface. In systemic circulation high calcium concentrations prevent systemic inflammatory side effects by stabilization of inactive (S100A8/S100A9)₂ tetramers (5) which, however, are useful biomarkers for monitoring local disease activity.