Proteases and Their Receptors in Inflammation (Progress in Inflammation Research)

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This monocyte migration is directed along a concentration gradient of MCP-1, via interaction with the monocyte receptor CCR2. Within the developing atheroma, the foam cells begin to secrete proinflammatory cytokines that maintain a chemotactic stimulus for adherent leukocytes, augment expression of scavenger receptors, and promote macrophage replication. However, macrophages are not alone in contributing to atheroma formation. T cells, dendritic cells, and mast cells are also recruited into atheromatous plaques.

Once within the arterial intima, T cells may become activated by encountering antigens such as ox-LDL and begin to secrete cytokines that can influence macrophage activity. The evolution of a fatty streak toward a complex lesion is typified by the proliferation of smooth muscle cells SMCs , their migration toward the intima, and their synthesis of collagen. Continued release of cytokines, such as MCP-1, by activated ECs, T cells, and foam cells not only perpetuates inflammation and lipid accumulation within the atheroma but also influences SMC activity.

Neovascularization supports plaque growth, and rupture of these newly formed, fragile vessels is postulated to result in an acute expansion of the lesion. The thinning of the fibrous cap is enhanced by the overexpression of MMPs, interstitial collagenases, and gelatinases, which degrade supportive collagen.

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Once the fibrous cap is weakened, the plaque is vulnerable to rupture, precipitating acute thrombotic complications. Disruption of the vulnerable atherosclerotic plaque, on exposure to hemodynamic stresses, can trigger thrombosis, culminating in acute myocardial infarction. Erosion of the plaque surface, characterized by areas of EC desquamation, exposes a prothrombotic surface. An even greater prothrombotic stimulus arises from the rupture of a fibrous cap and the spilling of its contents into the lumen. Subendothelial collagen, TF, and von Willebrand factor become accessible to components in the circulation, promoting coagulation and thrombin formation.

In response to this vascular insult, thrombogenicity is further favored by the activation of protease-activated receptors on platelets and in the adjacent tissue. Amid the surge of inflammation research, one singular observation that has generated extraordinary interest is the acute-phase reactant CRP.

Accumulating evidence suggests that circulating high-sensitivity CRP represents one of the strongest independent predictors of vascular death in a number of settings. This dogma has been recently revisited, with observations from our group and others suggesting that CRP has a direct effect to promote atherosclerotic processes and EC inflammation Figure 1.

Palusinski et al, unpublished observations, The proatherosclerotic effects of CRP also appear to be modified by risk factors and treatment strategies. For example, hyperglycemia potentiates the effects of CRP on EC activation, 38 and pharmacological interventions with statins, glitazones, and bosentan, an endothelin receptor antagonist, attenuate these processes.

Significance

In addition to having direct effects to promote EC activation, CRP appears to function in a fashion that inhibits bone marrow—derived endothelial progenitor cell survival and differentiation. Download figure Download PowerPoint Figure 1. CRP, inflammation, and endothelial activation. Accumulating evidence suggests that high-sensitivity CRP levels are one of the most powerful predictors of atherosclerosis and vascular death, offering prognostic value exceeding that of LDL cholesterol.

The mechanistic basis of the predictive value of CRP may be its ability to incite endothelial dysfunction. In this vein, recent studies demonstrate that CRP can decrease eNOS mRNA, augment ET-1, and upregulate diverse adhesion molecules and chemoattractant chemokines, uncovering a proinflammatory and proatherosclerotic phenotype. CRP therefore appears to function as an important circulating marker of endothelial dysfunction. The direct proatherogenic effects of CRP extend beyond the endothelium to the vascular smooth muscle.

Recent evidence suggests that CRP, at concentrations known to predict cardiovascular events, directly upregulates angiotensin type 1 receptor in vascular SMCs in vitro and in vivo, and stimulates vascular smooth muscle migration, proliferation, neointimal formation and ROS production. Endothelial dysfunction and the subsequent changes in blood flow promote CDmediated endothelial activation by decreasing the intracellular expression of a CD40 signaling blocker.

CD40L-induced pathways contribute to conditions that favor plaque progression toward instability. The balance between the synthesis and breakdown of collagen, the predominant structural component of the fibrous cap, is shifted toward degradation by CD40 ligation. Furthermore, CD40 has recently been shown to be constitutively expressed on the surface of platelets and that its ligation results in platelet activation, which may serve to further enhance platelet-driven thrombus formation. Download figure Download PowerPoint Figure 2. This signaling also results in upregulation of cellular adhesion molecules and secretion of chemokines that promote leukocyte recruitment.

The activated platelets generate more sCD40L, reinforcing the inflammatory reaction. IL is highly expressed in atherosclerotic plaques, as compared with normal arteries and is localized mainly in plaque macrophages. If the action of IL was inhibited, using a murine IL binding protein, fatty streak development was prevented and plaque progression was delayed in apolipoprotein E—deficient mice.

The proinflammatory IL may participate in all stages of plaque development. Download figure Download PowerPoint Figure 3. IL and plaque formation. IL orchestrates the cytokine cascade, accelerating atherosclerosis and plaque vulnerability. IL also promotes adhesion molecule expression on the endothelium and promotes plaque instability by enhancing MMP secretion. As alluded to earlier, blockade of IL action delayed atherosclerotic plaque progression; however, it also led to a stable plaque phenotype by decreasing macrophage, T-cell, and lipid content while increasing SMC and collagen content.

Recently, weight loss has also been shown to reduce circulating IL levels. Over the past few years, it has become increasingly clear that inflammation is at the root of atherosclerosis and its complications. Several other novel markers, associated with atherosclerosis, will be highlighted in the second part of this two-part series. This article is Part I of a 2-part article. Part II will appear in the October 28, , issue of Circulation.

Home Circulation Vol. View PDF. Tools Add to favorites Download citations Track citations Permissions. Improving patient adherence with asthma self-management practices: what works? Ann Allergy Asthma Immunol. Inhaler competence in asthma: common errors, barriers to use and recommended solutions.

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Inflammation

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J Exp Med. CRTH2, an orphan receptor of T-helpercells, is expressed on basophils and eosinophils and responds to mast cell-derived factor s. FEBS Lett. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. Palomares O, Akdis CA. Chapter 28 - Immunology of the Asthmatic Immune Response.

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New insights into the role of the mast cell in asthma. Clin Exp Allergy.

Inflammation - Wikipedia

Monomeric IgE enhances human mast cell chemokine production: IL-4 augments and dexamethasone suppresses the response. Mast cell phenotype, location, and activation in severe asthma.

Bibliographic Information

Data from the Severe Asthma Research Program. Amin K. The role of mast cells in allergic inflammation. Cutting edge: differential production of prostaglandin D2 by human helper T cell subsets. J Immunol. Lipopolysaccharide induces macrophage migration via prostaglandin D 2 and prostaglandin E 2. J Pharmacol Exp Ther.