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Prof. Gerard Pasterkamp,
Atherosclerosis is an inflammatory disease. The role of the innate immune system in atherogenesis is relatively unexplored. Toll Like receptors recognise pathogen associated motifs that have been highly conserved during evolution. In the present paper the role of Toll Like receptors in arterial occlusive disease is discussed.
It is evident that atherosclerosis is a consequence of a complicated inflammatory process with immune reactions at the initiation and progression of this disease. Inflammatory cells, like T-lymphocytes and macrophages, play an important role in all stages of atherosclerotic lesion development. Other cells from the vessel wall, like endothelial cells and adventitial fibroblasts, are also able to act as immunological cells that elicit a pro-inflammatory response. The triggers and pathways of initiation and regulation of the immune responses in atherosclerotic disease are largely unknown.
In general, the human immune system has two closely related pathways to respond to potentially harmful agents: the innate and the adaptive immune recognition systems. The adaptive immune system involves dynamic adaptation to unique antigenic epitopes that are present in the environment. The innate immune response is the first line of defense in which pathogen motifs that are conserved during evolution, called pathogen-associated molecular patterns (PAMPs), are recognised. These PAMPs are expressed by pathogens but may also be part of human endogenously expressed proteins. A group of receptors that is capable of recognising these PAMPs are Toll-like receptors (TLRs). TLR activation induces the expression of a wide variety of genes encoding pro-inflammatory proteins. The most described ligand is bacterial lipopolysaccharide (LPS) that is recognised by TLR-4. In the atherosclerotic plaques of human coronary arteries, expression of TLR-4 has been described in macrophages, adventitial fibroblasts and endothelial cells. Expression of these innate immune receptors in atherosclerotic plaques has led to the hypothesis that these receptors are involved in the development and progression of the atherosclerotic disease. Indeed, activation of TLR4 in an atherosclerotic mouse model results in a significant increase in atherosclerotic plaque formation. In a non-atherosclerotic mouse model, TLR-4 activation results in a strong intimal hyperplasia response [1,2]. Next to this, knockout mouse studies show that lack of TLR-4 reduces atherosclerosis and gives a more stable plaque phenotype. Clinical studies have also been performed. The TLR4 polymorphism Asp299Gly is a single nucleotide polymorphism in the TLR4 gene which can be found in 5-10% of the normal population. In a population based study, 810 persons were retrospectively screened for the TLR4 polymorphism . As compared to a control group, patients with the polymorphism had a lower risk of developing carotid atherosclerosis during a five-year follow up and revealed less intima-media thickness in the common carotid artery. It merits careful consideration that conflicting results have also been reported. One remaining question will be which human endogenous ligands can be responsible for the stimulation of the vascular TLR-4 and subsequent arterial luminal narrowing.
To summarise, an innate immune response via Toll Like Receptors may be an important stimulus for atherosclerotic lesion development and plaque destabilisation. Future studies will reveal whether the TLRs could serve as a suitable target for intervention. At present no drugs that inhibit TLR signaling are yet available.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
Pasterkamp G, van Keulen JK, de Kleijn DPV. Role of Toll-like receptor 4 in the initiation and progression of atherosclerotic disease. Eur J Clin Invest 2004; 34-328-334. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15147329
Kiechl S, Lorenz E, Reindl M et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 2002;347:185-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12124407
Michelsen KS, Wong MH, Shah PK et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10679-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15249654