| Macrophages are innate immunity cells that play a critical role in the initiation, progression, and rupture of atherosclerotic plaques. Death of macrophages within atherosclerotic plaques requires activated caspases, a set of critical cell death mediators. Caspases are cysteinyl proteases that cleave at the aspartate residue of their substrates. In addition to the canonical functions of caspases in processing inflammatory cytokines and mediating apoptotic cell death, they have been shown to be involved in physiologic functions of multiple cell types without leading to cell death. Many physiologic functions of macrophages require significant cytoskeletal re-arrangements similar to changes within a cell undergoing caspase-mediated apoptotic cell death. Activated caspases within macrophages are involved in the restructuring of the cytoskeleton of macrophages during differentiation, adhesion, chemotaxis, and fusion. Inhibition of caspases during the differentiation of pro-myelocytic cells to neutrophils, monocytes, and macrophages suppress their ability to undergoing respiratory burst. During adhesion, Fas (CD95, a cell death receptor) activates its cell death pathways through its adaptor FADD, caspase-8, and then caspase-3, in macrophages without leading to cell death. Inhibition of caspase-3 or its substrate, ROCK-1, attenuate the chemotactic response of macrophages to monocyte chemoattractant protein-1 (MCP-1). An alternative pathway of activating caspase-8 and caspase-3 through caspase-2 may be used by macrophages to undergo pathologic cellular fusion. Inhibition of caspase-2, caspase-8, or caspase-3, completely disrupts macrophages from undergoing fusion, while mice lacking those caspases can form physiologically functional osteoclasts (multi-nucleated cells by fusing macrophages). Our results show that activated caspases play diverse roles in macrophages from performing physiologic functions of cellular differentiation, adhesion, and chemotaxis to pathologic fusion to cell death. |
