Page 975 - Clinical Immunology_ Principles and Practice ( PDFDrive )

942 Part seven Organ-Specific Inflammatory Disease

Pam3 E-selectin
HSVEC LTA ICAM Caspase 3
IL-8
+ ROS Caspase 7 Early
TLR 4h 24h stimulus
2
VE-cadherin
PMN

MPO/MMP
Hyaluronan Exposure Apoptosis
Late stimulus

CD44
NET
Thrombus
FIG 69.4 A Hypothetical Model of Plaque Erosion. Toll-like receptor (TLR) 2 stimulation on
endothelial cells (HSVEC [human saphenous vein endothelial cells]) with Pam3 or lipoteichoic
acid (LTA) has been reported to induce endothelial activation and apoptosis, as suggested by
increased levels of adhesion molecules (E-selectin, ICAM), interleukin-8, and caspases -3 and -7.
This process is markedly potentiated but not necessarily initiated by polymorphonuclear neutrophil
(PMN) and leads to endothelial damage and extracellular matrix (ECM) exposure. Hyaluronic acid,
a component of ECM, is a ligand for TLR2 and for the receptor CD44 and might be involved in
the propagation of the inflammatory process. In humans, eroded plaques typically harbor abundant
hyaluronan and proteoglycans. Thus hyaluronic acid could be considered a relevant TLR2 agonist.
Also, products from infectious microorganisms may operate to promote atherothrombosis through
this mechanism. MPO, myeloperoxidase; MMP, metalloproteinase; NET, neutrophil extracellular
trap; ICAM, intercellular adhesion molecule; ROS, reactive oxygen species.

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in local hemodynamics and atherosclerotic artery. Animal models activators for TLR2. Intense immunostaining for hyaluronan
have demonstrated that local vasoconstriction that precedes and its receptor, CD44, has been detected along the interface
myocardial ischemia is occasionally accompanied by intracoronary between luminal thrombus and eroded plaque compared with
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thrombosis with endothelial lesions resembling human plaque fissured or stable plaque. These data led to the intriguing
erosion. A role of the innate immune system in this process has hypothesis that the accumulation of hyaluronan along the plaque
also been proposed, specifically a possible involvement of may be involved, through CD44 activation, in the promotion of
neutrophils. Coculture of neutrophils with endothelial cells endothelial discontinuity, thrombus formation, and leukocyte
induced endothelial injury and triggered endothelial cell apoptosis. accumulation. The ligation of TLR2 has been shown to result
Plasma from patients with eroded culprit plaques exhibited in inflammation and endothelial apoptosis in a process that could
elevated systemic myeloperoxidase (MPO) levels, produced be markedly potentiated but not necessarily initiated by poly-
primarily by PMNs, compared with levels in patients showing morphonuclear leukocytes. A “two-step model” has been proposed
plaque fissure. Moreover, in postmortem coronary specimens, in which the first hit derives from TLR2 activation and leads to
eroded plaque showed a much higher density of MPO-positive an initial endothelial injury, with subsequent apoptosis and
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cells in luminal thrombi compared with fissured plaque. Endo- desquamation; the second hit is mediated by neutrophil recruit-
thelial cells overlying atherosclerotic lesions abundantly express ment, with propagation of the local process and amplification
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the pattern-recognition receptor TLR2. TLR2 has been localized of endothelial damage. In humans, eroded plaques typically
mostly in areas of disturbed blood flow, and animal models have harbor abundant hyaluronan and proteoglycans, and TLR2 ligands
shown that the inhibition of this receptor reduces endothelial typically include both endogenous and exogenous gram-positive
dysfunction by low shear stress. In lesions prone to erosion, derived hyaluronan. Thus it has been proposed that hyaluronic
lipoproteins and proteoglycans could serve as endogenous acid could be considered a disease-relevant TLR2 agonist, and