Figure 1. Model of ER stress-induced apoptosis in advanced lesional macrophages.

Advanced lesions contain a number of molecules and processes that are known ER stressors. Activation of the UPR in macrophages leads to elevated levels of CHOP, which through a pathway involving the CHOP target ERO1 and IP3R-mediated calcium release, leads to elevation in cytosolic calcium (Ca²⁺_i) and activation of CaMKII. CaMKII triggers apoptosis execution pathways through a number of mechanisms, including NADPH oxidase activation and subsequent ROS generation. In vivo evidence suggests that this scenario is necessary but not sufficient by itself for apoptosis. Rather, apoptosis in ER-stressed macrophages may require a “second hit” consisting of combinatorial pattern recognition receptor (PRR) activation, and there are many factors in advanced lesions that can activate PRRs. The mechanism by which PRR activation tips the balance toward apoptosis in ER-stressed macrophages involves amplification of apoptosis pathways, such as NADPH oxidase-mediated ROS generation, and suppression of ER stress-induced compensatory cell survival pathways. See text for details. (Illustration Credit: Cosmocyte/Cameron Slayden)