At sites of inflammation and in normal immune surveillance, chemokines direct leukocyte migration across the endothelium. Many cell types that are extravascular can produce chemokines, and for these mediators to directly elicit leukocyte migration from the blood, they would need to reach the luminal surface of the endothelium. This article reviews the evidence that endothelial cells are active in transcytosing chemokines to their luminal surfaces, where they are presented to leukocytes. The endothelial binding sites that transport and present chemokines include glycosaminoglycans (GAGs) and possibly the Duffy antigen/receptor for chemokines (DARC). The binding residues on chemokines that interact with GAGs are discussed, as are the carbohydrate structures on GAGs that bind these cytokines. The expression of particular GAG structures by endothelial cells may lend selectivity to the type of chemokine presented in a given tissue, thereby contributing to selective leukocyte recruitment. At the luminal surface of the endothelium, chemokines are preferentially presented to blood leukocytes on the tips of microvillous processes. Similarly, certain adhesion molecules and chemokine receptors are also preferentially distributed on leukocyte and endothelial microvilli, and evidence suggests an important role for these structures in creating the necessary surface topography for leukocyte migration. IntroductionA central feature of inflammatory diseases is the migration of leukocytes from the circulation, across the endothelium and the basement membrane, and into the affected tissue. This mechanism of extravasation is induced by chemokines (chemoattractant cytokines), which are a family of proinflammatory mediators produced at the inflammatory site. 1,2 As part of the migration process, circulating leukocytes must first adhere to the luminal surface of the endothelium. According to the current paradigm, this interaction involves the sequential engagement of leukocyte and endothelial adhesion molecules. First, selectins and their carbohydrate counterligands mediate leukocyte tethering and rolling. Then, leukocyte integrins and their ligands, including immunoglobulinlike intercellular adhesion molecules, mediate firm leukocyte adhesion. 3 Chemokines play a role in firm adhesion by activating integrins on the leukocyte cell surface. 4,5 The leukocytes are directed by chemoattractant gradients to migrate across the endothelium, and through the extracellular matrix into the tissue.The intent of this review is to focus on the endothelium and its role in transcytosing and presenting chemokines to blood leukocytes, resulting in leukocyte extravasation. The molecular nature of the endothelial binding sites that are proposed to transport and present chemokines are discussed. The mechanisms of chemokine transcytosis and presentation by endothelial cells are then fitted into the current model of how leukocytes emigrate into tissues at sites of inflammation. Chemokine-binding sites on the endotheliumIt has been traditionally held that c...
Recent studies have demonstrated that neutrophils are not a homogenous population of cells. Here, we have identified a subset of human neutrophils with a distinct profile of cell-surface receptors [CD54(high), CXC chemokine receptor 1(low) (CXCR1(low))], which represent cells that have migrated through an endothelial monolayer and then re-emerged by reverse transmigration (RT). RT neutrophils, when in contact with endothelium, were rescued from apoptosis, demonstrate functional priming, and were rheologically distinct from neutrophils that had not undergone transendothelial migration. In vivo, 1-2% of peripheral blood neutrophils in patients with systemic inflammation exhibit a RT phenotype. A smaller population existed in healthy donors ( approximately 0.25%). RT neutrophils were distinct from naïve circulatory neutrophils (CD54(low), CXCR1(high)) and naïve cells after activation with formyl-Met-Leu-Phe (CD54(low), CXCR1(low)). It is important that the RT phenotype (CD54(high), CXCR1(low)) is also distinct from tissue-resident neutrophils (CD54(low), CXCR1(low)). Our results demonstrate that neutrophils can migrate in a retrograde direction across endothelial cells and suggest that a population of tissue-experienced neutrophils with a distinct phenotype and function are present in the peripheral circulation in humans in vivo.
The major envelope antigen of vaccinia virus is an acylated protein of M(r) 37,000 (p37K) which is required for the formation of extracellular enveloped virions (EEV). Despite its important role in the wrapping process, p37K has not been studied in much detail. In order to better characterize this protein we have undertaken a detailed biochemical analysis. Sodium carbonate treatment showed that p37K is tightly bound to the viral envelope. Its resistance to proteinase K digestion indicates that it is not exposed on the surface of EEV but lines the inner side of the envelope. Since p37K does not contain a signal peptide characteristic of most membrane proteins, we examined the possibility that the protein acquires its membrane affinity through the addition of fatty acids. Indeed, Triton X-114 phase partitioning experiments demonstrated that p37K is hydrophobic when acylated, but hydrophilic in the absence of fatty acids. Three other viral proteins have been shown to be required for virus envelopment and release from the host cell and we therefore tested whether p37K interacts with viral proteins. In EEV and in absence of reducing agents, an 80-kDa complex reacting with an anti-37K antiserum was found. Analysis of this complex showed that it most likely consists of a p37K homodimer. Interestingly, only a small amount of p37K occurs as a complex, most of it is present in the viral envelope as monomers.
BackgroundFibrocytes are bone-marrow derived cells, expressing both haematopoietic and stromal cell markers, which contribute to tissue repair as well as pathological fibrosis. The differentiation of fibrocytes remains poorly characterised and this has limited understanding of their biology and function. In particular two methods are used to generate fibrocytes in vitro that differ fundamentally by the presence or absence of serum.Methodology/Principal FindingsWe show here that fibrocytes grown in the absence of serum (SF) differentiate more efficiently from peripheral blood mononuclear cells than CD14+ monocytes, and respond to serum by losing their spindle-shaped fibrocyte morphology. Although fibrocytes generated in the presence of serum (SC) express the same range of markers, they differentiate more efficiently from CD14+ monocytes and do not change their morphology in response to serum. Transcriptional analysis revealed that both types of fibrocyte are distinct from each other, fibroblasts and additional monocyte-derived progeny. The gene pathways that differ significantly between SF and SC fibrocytes include those involved in cell migration, immune responses and response to wounding.Conclusions/SignificanceThese data show that SF and SC fibrocytes are distinct but related cell types, and suggest that they will play different roles during tissue repair and fibrosis where changes in serum proteins may occur.
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