Fig. 1

Processes involved in particle-induced pro-IL-1β expression. Pro-IL-1β expression requires intermediary mediators (signal 1). Silica-damaged macrophages or structural cells release intracellular proteins called alarmins that possess inflammatory activities once present in the extracellular environment. HGMB1 (High mobility group box-1), S100 and HSP (Heat shock proteins) proteins bind to multi-ligand receptors such as RAGE (Receptor for advanced glycation endproducts) or TLRs (Toll-like receptors) and stimulate the NFkB (transcription factors nuclear factor-kB)/AP-1 (Activator protein 1) pathway, leading to pro-IL-1β expression by surrounding macrophages. IL-1α and IL-33, two members of the IL-1 family, also pass across damaged cell membranes and bind their specific receptors, IL-1RI and ST2 (Interleukin 1 receptor-like 1), respectively. Additionally, other cytokines that are not classified as alarmins but known to promote pro-IL-1β production via NFkB/AP-1 activation (i.e., TNF-α and IL-1β itself) also participate in the expression of pro-IL-1β and synergize with alarmins