β2-Integrins – Regulatory and Executive Bridges in the Signaling Network Controlling Leukocyte Trafficking and Migration

Abstract

Leukocyte trafficking is an essential process of immunity, occurring as leukocytes travel within the bloodstream and as leukocyte migration within tissues. While it is now established that leukocytes can utilize the mesenchymal migration mode or amoeboid migration mode, differences in the migratory behavior of leukocyte subclasses and how these are realized on a molecular level in each subclass is not fully understood. To outline these differences, first migration modes and their dependence on parameters of the extracellular environments will be explained, as well as the intracellular molecular machinery that powers migration in general. Extracellular parameters are detected by adhesion receptors such as integrins. β2-integrins are surface receptors exclusively expressed on leukocytes and are essential for leukocytes exiting the bloodstream, as well as in mesenchymal migration modes, however, integrins are dispensable for the amoeboid migration mode. Additionally, the balance of different RhoGTPases – which are downstream of surface receptor signaling, including integrins – mediate formation of membrane structures as well as actin dynamics. Individual leukocyte subpopulations have been shown to express distinct RhoGTPase profiles along with their differences in migration behavior, which will be outlined. Emerging aspects of leukocyte migration include signal transduction from integrins via actin to the nucleus that regulates DNA status, gene expression profiles and ultimately leukocyte migratory phenotypes, as well as altered leukocyte migration in tumors, which will be touched upon.

Targeting integrin pathways: mechanisms and advances in therapy

“…Among them, integrins containing the β2 subunit are most abundant in leukocytes; therefore, integrin β2 is also called a leukocyte integrin. 86 …”

“… 87 , 88 Selectins expressed on leukocytes then bind with their ligands on vascular endothelial cells, which makes leukocytes adhere to the vascular endothelium and start fast rolling. 86 This process provides enough time for integrins to bind with their ligands. Integrins αLβ2 (bound to intercellular adhesion molecule [ICAM]-1), αMβ2 (bound to ICAM-2), and α4β1 (bound to vascular cell-adhesion molecule [VCAM]-1) are activated, slowing the rolling of leukocytes.…”

“…Integrins αLβ2 (bound to intercellular adhesion molecule [ICAM]-1), αMβ2 (bound to ICAM-2), and α4β1 (bound to vascular cell-adhesion molecule [VCAM]-1) are activated, slowing the rolling of leukocytes. 86 As leukocytes stop in the vascular endothelium, active integrin αLβ2 and αMβ2 induce leukocyte spreading and crawling toward infection. 89 Leukocytes that reach the site of infection cross the vascular endothelium and enter infected tissue with the participation of integrin α6β1, thereby mediating the inflammatory response.…”

“… 89 Leukocytes that reach the site of infection cross the vascular endothelium and enter infected tissue with the participation of integrin α6β1, thereby mediating the inflammatory response. 86 , 89 …”

Editorial: Adhesion molecules and autoimmune diseases

“…However, Efalizumab was withdrawn later due to JC virus reactivation in some patients; therefore, better understanding the roles of β2 integrins may help guide more effective therapeutics. In a comprehensive overview, Carla Guenther ( 1 ) depicted the role of β2 integrins in leukocyte recruitment. This review summarized the involvement of β2 integrins in the migration of each type of leukocyte with a view on signaling, what mode of migration has been described in which context, and their binding partners.…”