Expansion of Circulating Toll-Like Receptor 4–Positive Monocytes in Patients With Acute Coronary Syndrome

Abstract

Background— Atherosclerosis is an inflammatory disease in which monocytes and macrophages have been suggested to play an essential role. The underlying signaling mechanisms are unknown thus far. We hypothesized that the human isoform of Toll-like receptor (hTLR)-4 is involved in monocyte activation of patients with accelerated forms of atherosclerosis. Methods and Results— Expression of hTLR4 on circulating monocytes from 30 controls, 20 patients with stable angina (SA), 40 patients with unstable angina (UA), and 28 patients with acute myocardial infarction (AMI) was compared with the use of flow-cytometry and reverse transcription–polymerase chain reaction. Regulation of interleukin (IL)-12 and B7-1 as downstream events of TLR4 activation was analyzed after lipopolysaccharide stimulation of monocytes. TLR4-transfected Chinese hamster ovary (CHO) cells were used to identify potential hTLR4 ligands in the serum of patients with UA or AMI. Circulating hTLR4 + /CD14 + monocytes were ≈2.5-fold increased above controls and patients with SA in the UA and AMI groups ( P <0.0001). This was paralleled by enhanced transcript levels of TLR4 and Myd88 in patients with UA and AMI ( P <0.0001) and increased expression of IL-12 (UA 35.5±7.8, AMI 31.8±7.7 versus SA 2.2±0.5, controls 2.1±0.3 pg/mL; P <0.0002) and B7-1 (UA 27.3±14.4, AMI 22.6±11.1 versus SA 3.4±2.5, controls 2.4±2.3%; P <0.0001). Compared with serum from patients with UA and AMI, challenging TLR4-transfected CHO cells with serum from SA patients yielded only a weak response ( P <0.0001). Coincubation with anti–heat shock protein 60 inhibited CHO cell activation. Conclusions— UA and AMI are associated with enhanced expression and signaling events downstream of hTLR4 in circulating monocytes. These observations suggest hTLR4 activation as a signaling mechanism in immune-mediated progression of atherosclerosis.

Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-α and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque

“…43 Likewise, enhanced TLR4 expression has been suggested as a signaling mechanism for immune-mediated progression of atherosclerosis. 12 Our data suggest ( Figure 7) that viral infections trigger pDCs through TLR9 to secrete IFN-␣ in the atherosclerotic plaque. Furthermore, IFN-␣ enhances the expression of TLR4 on APCs with both pDC and mDC populations localized in close vicinity in the rupture-prone shoulder region.…”

“…9 TLR4 plays a pivotal role in plaque inflammatory activation. Circulating monocytes overexpress TLR4 during acute coronary syndrome, 12 and TLR4 is expressed in atherosclerotic plaques. 13,14 Apolipoprotein E knockout mice lacking TLR4 develop reduced atherosclerotic lesions, 15 and a TLR4 genetic variation is associated with diminished risk of atherosclerosis.…”

Citokin 's profile of mononuclearsat patients by myocardialin farction, complicated cardiacinsufficiencycitokin 's profile of mononuclearsat patients by myocardialin farction, complicated cardiacinsufficiency

“…Надалі цей чинник транслокуєть-ся в ядро клітини і активує гени цитокінів, результатом чого є секреція прозапальних інтерлейкіну-6 (ІЛ-6), ІЛ-8, фактора некрозу пухлин α (ФНП-α), а також регулюючого цей процес протизапального ІЛ-10. Таким чином моноцити залучаються до запального каскаду при ГІМ [5,13]. У цьому процесі активно беруть участь і лімфоцити.…”

Variants of Toll-like Receptor 4 Predict Cardiac Recovery in Patients with Dilated Cardiomyopathy

“…Moreover, pharmacological inhibition of TLR4 in mouse models of myocardial ischemia exerts beneficial therapeutic effects (16). In patients with coronary artery disease, the peripheral contents of TLR4-positive monocytes were significantly increased during acute myocardial ischemia (17). Despite the association between TLR4 * This work was supported by Transregional Collaborative Research Centre of expression and cardiovascular diseases, two genetic variants of this receptor (rs4986790, TLR4 c.1187A3 G, p.299D3 G and rs4986791, TLR4 c.1487C3 T, p.T399I) have been investigated in a number of studies focusing on atherosclerosis to include coronary artery disease.…”