The migration of leukocytes or WBCs (White Blood Cells) from the vascular system to sites of pathogenic exposure is a key event in the process of inflammation. The inflammatory reaction enables the organism to defend itself against infectious microbes. The entry of leukocytes into sites of injury or infection requires molecular mechanisms that enable the leukocytes to recognize such sites from within the vasculature and to form contact with the endothelium in order to exit and migrate through the blood vessel wall. Recognition as well as contact formation is mediated by several cell adhesion molecules which act in a sequential manner in concert with regulatory mediators such as the chemokines. The cell adhesion molecules that are involved in this process belong to three gene families: the selectins, the integrins, and members of the immunoglobulin super gene family. The mechanism of cell adhesion and transmigration vary according to the nature of the blood vessels and type of leukocytes (granulocyte or agranulocyte). Adhesion and diapedesis of granulocytes (which include neutrophils, basophils and eosinophils) have mostly been analyzed in context to non-lymphoid endothelium (Ref. 1 & 2). The PMNs (Polymorphonuclear Neutrophils) are the first line of host defense against infection by bacterial pathogens and are rapidly recruited to sites of bacterial invasion. Because the majority of pathogens are encountered at mucosal surfaces, PMNs must migrate out of the circulation, through the interstitium, and across to engage offending microbes. Although eosinophils and basophils are the least abundant circulating leukocytes, an increasing body of evidence suggests that the latter play an active pathogenic role in allergic inflammation by releasing diverse pro-inflammatory mediators, including vasoactive amines, cysteinyl leukotrienes and cytokines (Ref. 3 & 4).

An inflammatory response induced by infection, injury or an allergen triggers granulocytes to move into tissues towards the foreign invader, in a process called extravasation. In general, extravasation of leukocytes is a multi-step process that involves tethering, rolling and activation, firm adhesion to the endothelium, diapedesis and finally, transendothelial migration (also known as transmigration), the least characterized step in the process. The resting endothelium is normally impermeable to leukocytes; thus, during inflammation, intracellular signals that modulate endothelial permeability are activated to facilitate the paracellular passage of leukocytes. Extravasation of granulocytes requires specific cell-cell contacts between granulocytes and endothelial cells lining the blood vessel (Ref. 5). Granulocytes normally circulate in the blood unattached and in response to inflammatory signals such as TNFs (Tumor Necrosis Factors), interleukins, complement components, GCSF (Granulocyte Colony Stimulating Factor), histamine, etc. They adhere to the surface of endothelium and then crawl forward (diapedesis) and pass between neighboring endothelial cells (transmigration) to reach the infected tissues. These inflammatory signals induce endothelial cells to exocytose P-selectin and E-selectin and enhance release of chemokines through transcytosis. These inflammatory signals are conveyed via GPCRs (G-Protein-Coupled Receptors), which are known to mediate rapid cellular responses (Ref. 6).

At the initial stage, the selectins mediate the initiation of the cell contact between granulocytes and endothelial cells. The P-selectin and E-selectin bind to their respective ligands, PSGL1 (P-Selectin Glycoprotein Ligand) and ESL1 (E-Selectin Ligand-1), on the ganulocytes. L-selectins are also recognized by E-selectins and act as ligands. L-selectin occurs only on leukocytes. Besides these, oligosaccharides on the granulocyte cell surface like the SLe (Sialyl Lewis) structures also bind to the selectins. However, this adhesion is weak and the granulocyte rolls along the endothelial cells. This selectin-mediated tethering of granulocytes to the blood vessel wall in combination with the rapidly flowing bloodstream leads to a rolling movement of the granulocytes on the non-lymphoid endothelial cell surface. In contrast to the rapidly flowing cells in the bloodstream, the rolling cells are able to sense signals from the endothelium, which stimulates them to adhere more firmly to the endothelial cell surface. Such signals are given by chemokines and fMLP (N-formyl-Met-Leu-Phe) through CXCRs (Chemokine (C-X-C) Receptors)/CCRs (Chemokine-CC-Motif Receptors) and fMLPRs (fMLP Related Receptors), respectively, and G-proteins. Often the chemokines like SDF1 (Stromal Cell-Derived Factor-1) are presented and immobilized by Sdcs (syndecans), cell surface proteoglycans, on the endothelium (Ref. 2 & 7). These stimulatory effects cause activation of integrins, which bind to members of the immunoglobulin superfamily on the endothelial cell surface. The major integrins involved in this process are LFA1 (Leukocyte Function-Associated Antigen-1) (a complex of Itg-AlphaL (Integrin-Alpha-L) and Itg-Beta2 (Integrin-Beta-2)), Mac1 (comprised of Itg-AlphaM and Itg-Beta2), and Itg-Alpha9 (Integrin-Alpha-9)/Itg-Beta1 (Integrin-Beta-1), which bind to members of the immunoglobulin superfamily such as ICAM1 (Intercellular Adhesion Molecule-1), ICAM2 and VCAM1 (Vascular Cell Adhesion Molecule-1) on the non-lymphoid endothelial cell surfaces. This causes tight adherence of granulocytes to the endothelium. Adhesion via activated integrins is a prerequisite for the active migration of leukocytes on the endothelial cell surface and finally through the layer of endothelial cells (Ref. 8).

Cross-linking of integrins with ICAMs and VCAM1 activates the ERM (Ezrin, Radixin, Moesin) proteins and recruits Thy1 (Thy1 Cell Surface Antigen) to the cell surface. This process further stimulated by the plasma glycoprotein, fibrinogen. This interaction enables binding of PECAM1 (Platelet Endothelial Cell Adhesion Molecule-1) and also facilitates attachment of junctional adhesion proteins like JAM2 (Junctional Adhesion Molecule-2) and JAM3 with the granulocyte integrins. These cross-linking results in the docking of granulocytes to the apical surface of the endothelial cell and triggers signals through generation of ROS (Reactive Oxygen Species) and formation of stress fibers (altering actin and myosin structures) that further results in the activation of MMPs (Matrix Metalloproteinases). Activated MMPs and ROS degrade the assembly of junctional proteins like VEC (Vascular Endothelial Cadherin) and other CAMs (Cellular Adhesion Molecules), leading to the opening of inter-endothelial cell contacts and allowing granulocytes to transmigrate (Ref. 9 & 10). The adhered granulocyte thus migrates between adjacent endothelial cells to reach the underlying tissue. It is still a matter of concern whether leukocytes transmigrate through the junctions between adjacent endothelial cells or directly through a single endothelial cell. The unique interactions between activated granulocytes and endothelial cells, despite their complexity, helps to demonstrate the interplay between cell-surface molecules, intracellular signaling cascades, and the control of motility and cell-cell adhesion (Ref. 3 & 11).


Granulocyte Adhesion and Diapedesis


Pathway Key

Related products

  1. CD4 T cells: fates, functions, and faults. Zhu J, Paul WE.Blood. 2008 Sep 1;112(5):1557-69.
  2. Imbalance in Th cell polarization and its relevance in type 1 diabetes mellitus. Sia C.Rev Diabet Stud. 2005 Winter;2(4):182-6.
  3. Immunological decision-making: how does the immune system decide to mount a helper T-cell response? Kaiko GE, Horvat JC, Beagley KW, Hansbro PM.Immunology. 2008 Mar;123(3):326-38.
  4. Differentiation of effector CD4 T cell populations (*). Zhu J, Yamane H, Paul WE.Annu Rev Immunol. 2010 Mar;28:445-89.
  5. An insight into molecular mechanisms of human T helper cell differentiation. Rautajoki KJ, Kylaniemi MK, Raghav SK, Rao K, Lahesmaa R.Ann Med. 2008;40(5):322-35.
  6. GATA3 up-regulation associated with surface expression of CD294/CRTH2: a unique feature of human Th cells. De Fanis U, Mori F, Kurnat RJ, Lee WK, Bova M, Adkinson NF, Casolaro V.Blood. 2007 May 15;109(10):4343-50.