Table 1. Evidence that ER stress-induced macrophage (Mφ) apoptosis and defective efferocytic clearance of apoptotic Mφs are important in advanced plaque progression in mouse models of atherosclerosis.

A. Models affecting ER stress-induced Mφ apoptosis
Mouse model	Description of mutation	Weeks on high-fat diet	Effect of mutation on Mφ apoptosis and plaque necrosis in advanced aortic root lesions
Npc1+/−;Apoe−/−81	NPC1 is a protein involved in intracellular cholesterol trafficking. The heterozygous mutation results in a partial defect of cholesterol trafficking to the ER, and thus protects the ER from cholesterol-induced ER stress	18, 25	↓
Stat1−/− → Ldlr−/−*82	STAT1 is activated during ER stress and promotes Mφ apoptosis	10, 12	↓
Chop−/−;Apoe−/−83 Chop−/−;Ldlr−/−83	CHOP is induced during ER stress and triggers apoptosis in ER-stressed Mφs	10, 12	↓
Insr−/− → Ldlr−/−85	Mφs lacking insulin receptors, as a model of Mφ insulin resistance, undergo ER stress and are more susceptible to ER stress-induced apoptosis	8, 12	↑
Sra−/−;Cd36−/−; Apoe−/−88	Activation of the type A scavenger receptor (SRA) and CD36 synergize with ER stress to cause apoptosis in Mφs	12	↓
p38afl/fl;LysMCre+/−; Apoe−/−89	ER stress activates p38 in Mφs, which can trigger a compensatory cell survival pathway through activation of Akt	9	↑
B. Models affecting efferocytosis
Mouse model	Description of mutation	Weeks on high-fat diet	Effect of mutation on Mφ apoptosis and plaque necrosis in advanced aortic root lesions
Tg2−/− → Ldlr−/−102	Transglutaminase 2 mediates recognition of apoptotic cells by efferocytic Mφs	16	↑
Mfge8−/− → Ldlr−/−103	MFG-E8 is a molecule that can bridge apoptotic cells and efferocytes, thus facilitating efferocytosis	8, 15, 20	↑
MertkKD;Apoe−/−104, 105	Mertk is a receptor on efferocytes for apoptotic cells. The KD mutation renders the receptor non-functional	8, 10, 15, 16	↑
Gld;Apoe−/−106	The Gld mutation inactivates the ligand for the Fas receptor. Mice with this mutation acquire an autoimmune syndrome characterized by defective efferocytosis.	12	↑

^*This designation indicates transplantation of bone marrow from mutant mice into lethally irradiated Ldlr−/− mice to create chimeric mice in which only bone marrow-derived cells carry the mutation. Bone marrow from wild-type mice are used for the control arm in these types of studies. For atherosclerosis studies using this method, the major type of lesional cell carrying the mutation is the macrophage.