Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E

Abstract

Toll-like receptors (TLRs) and the downstream adaptor molecule myeloid differentiation factor 88 (MyD88) play an essential role in the innate immune responses. Here, we demonstrate that genetic deficiency of TLR4 or MyD88 is associated with a significant reduction of aortic plaque areas in atherosclerosis-prone apolipoprotein E-deficient mice, despite persistent hypercholesterolemia, implying an important role for the innate immune system in atherogenesis. Apolipoprotein E-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was associated with reductions in circulating levels of proinflammatory cytokines IL-12 or monocyte chemoattractant protein 1, plaque lipid content, numbers of macrophage, and cyclooxygenase 2 immunoreactivity in their plaques. Endothelial-leukocyte adhesion in response to minimally modified low-density lipoprotein was reduced in aortic endothelial cells derived from MyD88-deficient mice. Taken together, our results suggest an important role for TLR4 and MyD88 signaling in atherosclerosis in a hypercholesterolemic mouse model, providing a pathophysiologic link between innate immunity, inflammation, and atherogenesis.

Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions

“…[25][26][27][28] Given the involvement of NFkB signaling in atherosclerosis, LPS was used to activate it and stimulate the production of NFkBdependent pro-inflammatory cytokines. 29,30 Indeed, LPS caused a sustained activation of p65 in THP-1 macrophages ( Fig.…”

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

“…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. 16 Apart from microbial molecules such as lipopolysaccharides, autoantigens found in the plaque environment are also candidates for TLR4-dependent activation of APCs.…”

PPARγ agonist, rosiglitazone, regulates angiotensin II-induced vascular inflammation through the TLR4-dependent signaling pathway

“…[19][20][21] The TLR4 signaling activates mitogen-activated protein kinases and production of interferon-gamma-inducible protein 10 (IP-10), in turn activating protein kinase C (PKC) and finally resulting in the translocation of NF-kB. [22][23][24] Recent studies have revealed that the TLR4 signaling plays a central role in atherosclerosis, [25][26][27] thus providing an important link between inflammation, innate immunity and atherosclerosis. Although PPARg agonists exert anti-inflammatory and antiarteriosclerotic actions in the cardiovascular system, the exact mechanisms, whereby rosiglitazone affects Ang II-mediated inflammatory responses, and the TLR4-dependent signaling pathway involved are largely unknown.…”