Blood-induced joint damage. Mechanisms involved in IL-1β–mediated inflammation, cartilage damage, and synovial reaction after exposure to blood. Various PAMPs or DAMPs prime macrophages to activate NF-κB and induce expression of NLRP3, caspase-1, and IL-1β. Heme induces Syk and NADPH oxidase 2 (NOX2) activation to generate mtROS required for activation of NLRP3 to create the inflammasome for generating active caspase-1. This in turn generates active IL-1β from the macrophage to initiate the inflammatory response leading to cartilage damage. Other cytokines promote (such as IL-6) and inhibit (such as IL-10 and IL-4) inflammation. A separate set of events, probably initiated by TNFα and mediated by VEGFα, HIFα, SDF1α, and MMP9, lead to synovial inflammation, hyperplasia, and neoangiogenesis. DAMP, distress-associated molecular pattern; GAG, glycosaminoglycan; HIF1α, hypoxia-inducible factor 1α; MMP9, matrix metalloprotease 9; mtROS, mitochondrial reactive oxygen species; NF-κB, nuclear factor-κB; PAMP, pathogen-associated molecular pattern; RBC, red blood cell; SDF1α, stromal cell-derived factor 1α; VEGFα, vascular endothelial growth factor α. The figure is based on Dutra et al,⁷  Schlesinger et al,⁹  Sen et al,¹¹  and the article by van Vulpen et al beginning on page 2239.