Localization of Apoptotic Macrophages at the Site of Plaque Rupture in Sudden Coronary Death

145

124

Atherosclerotic lesions are infiltrated by macrophages and T lymphocytes, potentially reactive to pathogens. We studied in vivo activated T lymphocytes that infiltrate atherosclerotic plaques of Helicobacter pylori-infected patients with or without anti-Chlamydia pneumoniae antibodies. In all atherosclerotic lesions, T helper type 1 (Th1) cells were predominant. C. pneumoniae-specific T cells were detected only in the plaques of anti-C. pneumoniae seropositive patients, whereas H. pylori-specific T cells were found in the gastric mucosa but not in the plaques of the same patients. Plaque-derived Th1 cells expressed cytotoxicity, proapoptotic activity, and help for monocyte tissue factor production. Although multifactorial, atherosclerosis can be regarded as a Th1-driven immunopathological condition.

Section: Figmentioning

confidence: 99%

T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions

Benagiano

Azzurri

Ciervo

et al. 2003

145

124

“…Plaque necrosis is thought to promote lesion instability, leading to myocardial infarction, stroke, and peripheral vascular disease (3)(4)(5)(6)(7). Thus, advanced lesional macrophage apoptosis may be a critical step in benign-to-vulnerable plaque transformation.…”

mentioning

confidence: 99%

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Seimon

Obstfeld²,

Moore³

et al. 2006

164

194

Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticulum (ER)-stressed macrophages. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Tolllike receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-␤ branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-␤, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFN-␤. Thus, combinatorial signaling between two distinct PRRs results in a functional outcomemacrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical.apoptosis ͉ atherosclerosis ͉ scavenger receptor ͉ Toll-like receptor ͉ innate immunity

“…These necrotic areas are often found near sites of plaque rupture, which is directly linked to acute thrombosis, vascular occlusion, and tissue infarction (7). Indeed, the presence of apoptotic macrophages is associated specifically with ruptured atherosclerotic plaques in human coronary artery lesions (8). The mechanistic link between macrophage death and unstable plaques may be related to plaque-destabilizing enzymes, inflammatory mediators, and procoagulant and thrombogenic molecules released by these dying cells (2).…”

mentioning

confidence: 99%

Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis

Feng

Zhang

Kuriakose

et al. 2003

131

110

Macrophage death in advanced atherosclerotic lesions leads to lesional necrosis and likely promotes plaque instability, a precursor of acute vascular events. Macrophages in advanced lesions accumulate large amounts of unesterified cholesterol, which is a potent inducer of macrophage apoptosis. We have shown recently that induction of apoptosis in cultured macrophages requires cholesterol trafficking to the endoplasmic reticulum (ER). Moreover, macrophages from mice with a heterozygous mutation in the cholesterol-trafficking protein Npc1 have a selective defect in cholesterol trafficking to the ER and are protected from cholesterol-induced apoptosis. The goal of the present study was to test the importance of intracellular cholesterol trafficking in atherosclerotic lesional macrophage death by comparing lesion morphology in Npc1 ؉/؉ ;Apoe ؊/؊ and Npc1 ؉/؊ ;Apoe ؊/؊ mice. Although advanced lesions in Npc1 ؉/؉ ;Apoe ؊/؊ mice had extensive acellular areas that were rich in unesterified cholesterol and macrophage debris, the lesions of Npc1 ؉/؊ ;Apoe ؊/؊ mice were substantially more cellular and less necrotic. Moreover, compared with Npc1 ؉/؊ ;Apoe ؊/؊ lesions, Npc1 ؉/؉ ;Apoe ؊/؊ lesions had a greater number of large, TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling)-positive areas surrounding necrotic areas, indicative of macrophage apoptosis. These differences were observed despite similar total lesion area and similar plasma lipid levels in the two groups of mice. These data provide in vivo evidence that intact intracellular cholesterol trafficking is important for macrophage apoptosis in advanced atherosclerotic lesions and that the ERbased model of cholesterol-induced cytotoxicity is physiologically relevant. Moreover, by showing that lesional necrosis can be diminished by a subtle defect in intracellular trafficking, these findings suggest therapeutic strategies to stabilize atherosclerotic plaques.