Integrin activation in the immune system

Abstract

Modulation of leukocyte adhesiveness is critical to leukocyte function during the immune response. A central paradigm in this phenomenon is represented by integrin activation, which is controlled by inside-out signal transduction mechanisms triggered by selectins, chemoattractants and TcR-bound Ag and facilitated by mechanochemical forces. Integrins are heterodimeric adhesive receptors differently expressed on all leukocyte subtypes. At least two distinct modalities of integrin activation are known, namely conformational changes, leading to increased affinity, and lateral mobility leading to increased valency, both enhancing cell avidity (adhesiveness). Several signal transduction events have been correlated to integrin activation in leukocytes. The complexity of intracellular signaling networks leading to leukocyte integrin activation is likely functional to generate robustness and fine tuning of integrin activation allowing integration of qualitative and quantitative variations of extracellular signals leading to leukocyte-, agonist- and integrin-specific control of adhesion. In this context, the recent modular abstraction proposed for the functional architecture of biological networks may provide a powerful paradigm to understand regulation and specificity of signaling events. Accordingly, pro-adhesive intracellular signaling networks may be organized in regulatory signalosomes, or modules, corresponding to discrete clusters of interacting signaling proteins, with some devoted to context-dependent regulation of specificity and dynamics of integrin activation. The principles and technologies of systems biology, and more specifically of network theory, may help to address this complexity and unveil the inner logic governing leukocyte recruitment during the immune response.

CD81 is essential for the formation of membrane protrusions and regulates Rac1-activation in adhesion-dependent immune cell migration

“…The integrin activation process is still not fully understood but involves both conformational changes that are regulated by cytoplasmic signaling factors or components of the actin cytoskeleton, for example, talin, the kindlins, Rap1, or the cytohesins. Ligand-bound integrins engage in multiple intracellular signaling events that result in, eg, adhesion strengthening and F-actin-dependent cell shape changes (reviewed in [41][42][43] ). The activation of Rho GTPases is of central importance for this function, 34 and we consistently detected a selective loss of Rac1 activity in CD81-deficient DCs.…”

Distinct Binding Affinities of Mac-1 and LFA-1 in Neutrophil Activation

“…Physiologically, Mac-1 and LFA-1 are constitutively expressed on PMNs and initiate the slow rolling, firm adhesion, and transient crawling of PMNs via binding to ICAM-1 ligands expressed on activated endothelial cells under blood flow (7,10,11). Even with similar structures, Mac-1 and LFA-1 play distinct roles in leukocyte activation.…”

“…Inside-out signaling triggered by selectins and chemokines or outside-in signaling triggered by ligand binding induces integrins to undergo dramatic transition from bent low-affinity (LA) to extended intermediate-or high-affinity (HA) conformation, which leads to opening of the ligand-binding pocket. Binding of activated integrins to their ligands on endothelial cells favors neutrophil arrest and firm adhesion (1,2,7,10,11). Furthermore, Mac-1 and LFA-1 are found to respond diversely to different chemokines: Mac-1 is the dominant integrin involved in chemotaxis to fMLF, whereas LFA-1 is the major receptor involved in chemotaxis to IL-8 (21).…”

Node Interference and Robustness: Performing Virtual Knock-Out Experiments on Biological Networks: The Case of Leukocyte Integrin Activation Network

“…Integrin activation is mandatory to the completion of leukocyte recruitment and is regulated by chemoattractants, which, in turn, trigger an intricate network of signaling proteins devoted to integrin function modulation. Till now, at least 61 intracellular signaling molecules have been shown to be involved in positive or negative modulation of leukocyte adhesion [38], each one potentially interacting with a number of upstream regulators and downstream effectors. In this context, it is of pharmacological interest to be able to identify which proteins are most suitable for potential target anti-inflammatory therapies.…”