Aernoud Fiolet

25 General introduction and thesis outline First role of cholesterol crystals The components that lead to the activation of interleukin – 1 and interleukin – 6 are of equal importance in the initiation and proliferation of the inflammatory response, which can promote atherogenesis and degradation of the atherosclerotic cap. Pro– interleukin – 1 β is cleaved by caspase 1 to become the active form of interleukin – 1 β . Caspase 1 activity depends on a caspase 1–activating complex. Such complexes are inflammasomes, which are comprised of (a) caspase 1 or caspase 5, (b) an apoptosis-associated speck-like protein containing a C-terminal caspase-recruitment domain adaptor protein (ASC) and (c) members of cytoplasmic nucleotide-binding oligomerisation domain (NOD)-like receptors. (Figure 3) The combination of these proteins and receptors is abbreviated as “NALP” or “NLRP” inflammasome. Each inflammasome is activated by different stimuli. The NLRP3 inflammasome is the best characterised inflammasome. 75,76 The NLRP3 inflammasome can be activated by physiochemical stressors, microbiologic antigens, cell debris, and danger-associated molecular patterns of any kind. 77–80 Crystalline structures are one of the most striking activators of the NALP3- containing inflammasome (i.e. the NLRP3 inflammasome). Crystals are solid particles formed from ions or molecules that aggregate and are arranged in a regular, ordered structure. If these crystals tend to stick together, they can form calculi or stones. Common clinical examples include gallstones (cholelithiasis), kidney stones or ureter stones (nephrolithiasis or uretolithiasis, respectively), and salivary stones (sialothiasis). 81 A typical example of crystallised structures causing an inflammatory response is seen in gout, where hyperuricaemia leads to the precipitation of uric acid crystals, most prominently in the distal extremities, due to their relatively low temperatures. The inflammatory response following crystal deposition is marked by the release of activated interleukin – 1 and is dependent on the NLRP3 inflammasome. 82 The crystalline structure of silica crystals, aluminium salts, and asbestos all initiate similar NLRP3 inflammasome–mediated interleukin – 1 release. 83,84