Ebook Inflammation fundamental mechanisms: Part 2
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Ebook Inflammation fundamental mechanisms: Part 2
Chapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2here to the vascular endothelium and transmigrate to get access to the sire of inflammation.1"4 The leukocyte adhesion cascade describes leukocyte recruitment through postcapillary venules. It consists of margination, rolling, arrest, spreading, intraluminal crawling, transendothelial migration, and Ebook Inflammation fundamental mechanisms: Part 2 migration into the tissue. This sequence of events is common for adhesion for many types of leukocytes in many organs and tissues. However, it is notEbook Inflammation fundamental mechanisms: Part 2
universal: some leukocytes stop without rolling, and in some organs, capillaries rather than venules are the site of leukocyte adhesion. Leukocyte adChapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2ter will cover most of the molecular mechanisms and biomechanical constraints of all these forms of leukocyte adhesion except those relevant to atherosclerosis. Chemokines are important regulators of leukocyte adhesion through integrins.*La Jolla Institute for Allergy and Immunology.' Department of Ebook Inflammation fundamental mechanisms: Part 2Bioengineering, University of California San Diego.172 K. Ley & z. Fan1Leukocyte adhesion molecules1.1. IntegrinsIntegrins are activatable heterodimerEbook Inflammation fundamental mechanisms: Part 2
ic transmembrane molecules.4- Most integrins have almost no affinity for their ligands unless activated by inside-out signaling. In leukocytes, the moChapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2d by heterotrimeric G-proteins and are therefore called GPCRs.All leukocytes (used here as a term encompassing all white blood cells) express one or more members of the p2 (CD 18) integrin family. In fact, p2 integrins are also called leukocyte integrins, because they are leukocyte-specific and not Ebook Inflammation fundamental mechanisms: Part 2expressed in other cells. The a subunits of all p2 integrins contain an inserted I domain with homology to von Willebrand factor A domain. The I domaiEbook Inflammation fundamental mechanisms: Part 2
n is the ligand binding site and, upon ligand binding, interacts with the p I-like domain through an “internal ligand" that is exposed when the integrChapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2Mac-1 or CDllb/CD18), otxp2 integrin (CD1 1ỜCD18), and aDP2 integrin (CDlld/CD18). All leukocytes express LFA-1, although at different levels. Mac-1 is expressed on neutrophils, basophils, eosinophils, monocytes, and some activated T cell subsets. CDllc/CD18 is expressed on some monocytes, many macr Ebook Inflammation fundamental mechanisms: Part 2ophages, dendritic cells, as well as neutrophils, and some lymphocytes. CDl ld/CD18 expression is found on neutrophils, some T cell subsets, monocytesEbook Inflammation fundamental mechanisms: Part 2
, macrophages, and dendritic cells.The ligand specificities of LFA-1 and CD1 ld/CD18 are relatively narrow; those of Mac-1 and CDllc/CD18 are broad (TChapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2n 3), 2, and 4 and a multitude of other ligands. Similar to Mac-1, CD11ỜCD18 binds to multiple ligands beside ICAM-1, 2, 4 and Vascular cell adhesion protein 1 (VCAM-1), butLeukocyte Adhesion 173Table 1. p2 inregrins and parr of their ligands.Alternative nameMain ligandsƠ.LP2 CDlla/CD18; LFA-1ICAM-1 Ebook Inflammation fundamental mechanisms: Part 2"5-11’ ICAM-229’120 ICAM-3121 ICAM-4122,123 ICAM-5124’125 ESM-1126 JAM-18 Telencephalin127 Collagen116Ơ.MP2 CD1 lb/CD18; Mac-1ICAM-l128’130 ICAM-2131Ebook Inflammation fundamental mechanisms: Part 2
ICAM-4122 Fibrinogen132-134 Factor X135 Collagen116 iC3b’16-36 Heparin137 GPIba138 JAM-363 Thy-1139 Plasminogen140 EPCR141 Human leukocyte elastase142Chapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 202 CD1 lc/CD18; pl50,95ICAM-l150'151 ICAM-2152 ICAM-431 VCAM-1152 Fibrinogen151-133,154(Continued)174 K. Ley & z. FanTable 1. (Continued)Alternative nameMain ligandsƠ-D02CDlld/CD18Collagen116 iC3bl 16,151,155,156 Heparin157 GPIbơ.158 Thy-1159 Plasminogen160 Denatured proteins13 ICAM-3161VCAM-1162,16 Ebook Inflammation fundamental mechanisms: Part 23 Fibrinogen164 Vitronectin164 Cyr61164 Plasminogen164the affinities are poorly defined. CDlld binds ICAM-3, VCAM-1, and other ligands. CDl lb/CD18 anEbook Inflammation fundamental mechanisms: Part 2
d CD1 lc/CD18 are also complement receptors (CR3 and CR4, respectively) and can bind denatured proteins, such as proteins coated on a foreign, non-bioChapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2ocess is particularly well studied in p2 integrins. For example, the dynamic range of the affinity of LFA-1 for ICAM-1 is estimated to change 10,000-fold from resting to fully activated.1” p2 integrin activation is initiated by signaling events triggered by chemokines binding their G-protein coupled Ebook Inflammation fundamental mechanisms: Part 2 receptors (GPCRs). Through signaling intermediates, kindlin-3 and talin-1 are brought to the plasma membrane, where they bind the cytoplasmic tail ofEbook Inflammation fundamental mechanisms: Part 2
the P2 subunit. This induces two conformational changes: extension and high affinity (Figure 1). Extension and affinity change were originally thoughChapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2cussed in many excellent reviews.4'5,7,12p2 integrins are distributed all over the surface of leukocytes. However, extended and high-affinity (activated) p2 integrins areLeukocyte Adhesion 175 concentrated in small clusters, most of which sit on the tips of microvilli. LFA-1 is expressed on the plas Ebook Inflammation fundamental mechanisms: Part 2ma membrane and has no intracellular stores, whereas Mac-1 is expressed on the plasma membrane and on the membrane of neutrophil tertiary and secretorEbook Inflammation fundamental mechanisms: Part 2
y granules (see Chapter 6 for more detail). LFA-1 is highest on lymphocytes and patrolling monocytes, but also expressed on all other leukocytes. LFA-Chapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2 is highest on neutrophils and increases further (~ 10-fold) after degranulation, when the intracellular pool of Mac-1 is mobilized. This and the vast range of ligands suggest that Mac-1 mainly functions in the extracellular space. In human, but not mouse, neutrophils Mac-1 is also involved in arres Ebook Inflammation fundamental mechanisms: Part 2t. Like Mac-1, CDllc/CD18 can bind denatured proteins (hydrophobic amino acid sequences that arc normally buried inside properly folded proteins).13 OEbook Inflammation fundamental mechanisms: Part 2
ther than that, its function is unknown. The CDllc knockout mouse has some defects in lipid handling. The CD lid knockout mice showed defect in T cellChapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2 VLA-4) and a4p7 (CD49d/p7). The Ơ.4 integrins can also be activated, but the dynamic range of affinity for ligand seems to be lower than p2 integrins. is expressed on most leukocytes except naive T and B cells and at low levels on neutrophils. ơ.4Pị integrin binds endothelial VCAM-1 and alternative Ebook Inflammation fundamental mechanisms: Part 2ly spliced fibronectin. This integrin is involved in chorioallantoic fusion; the knockout mouse is therefore embryonic lethal. Conditional knockout miEbook Inflammation fundamental mechanisms: Part 2
ce and blocking monoclonal antibodies have shown that Ơ.4P1 integrin is important in monocyte, eosinophil, basophil, and activated lymphocyte traffickChapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2ells.2(X4P7 is expressed by monocytes and antigen-experienced T and B cells. The main ligand for (X4P7 integrin is Mucosal Addressin Adhesion Molecule-1 (MAdCAM-1), which is exclusively expressed in the gastrointestinal tract. This organ specificity has spawned the176 K. Ley & z. FanFig. 1. Leukocyt Ebook Inflammation fundamental mechanisms: Part 2e recruitment. Most rolling leukocytes (blue, right) are neutrophils (indicated by pale granules and tabulated nucleus) and make long, thin tethers thEbook Inflammation fundamental mechanisms: Part 2
at stabilize selectin-mediated rolling by PSGL-1 binding endothelial P-selectin (insert). 10-15% of these tethers swing around and become slings, selfChapter 5Leukocyte AdhesionKlaus Ley*'f and Zhichao Fan*Leukocyte adhesion is central to all forms of inflammation, because all leukocytes need to adh Ebook Inflammation fundamental mechanisms: Part 2 surface, leukocytes arrest by activating 02 integrins (second cell from right). The top of the insert shows a schematic of integrin activation, where high affinity is green, extended is red, and extended high affinity is yellow. Only extended high-affinity integrin can bind ligands like ICAM-1 in t Ebook Inflammation fundamental mechanisms: Part 2rans (on rhe endothelial cell). The bottom of the insert shows live cell imaging data where the integrin conformations are detected by reporter antiboEbook Inflammation fundamental mechanisms: Part 2
dies and mapped on the bottom surface of rhe arresting neutrophil using total internal reflection microscopy (green, red, and yellow indicate the highGọi ngay
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