Rheostat regulation of integrin-mediated leukocyte adhesion
Ivor S. Douglas, Themistocles Dassopoulos
Ivor S. Douglas, Themistocles Dassopoulos
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Commentary

Rheostat regulation of integrin-mediated leukocyte adhesion

Abstract

The homing of activated T lymphocytes to the gut in inflammatory bowel diseases is dependent on their coordinated, integrin-mediated adhesion and de-adhesion to substrates and blood vessel walls. In this issue of the JCI, Park and colleagues reveal a key modulatory role of a binding site within β integrins, known as the ADMIDAS domain, in controlling integrin de-adhesion in mice (see the related article beginning on page 2526). These observations add to our growing understanding of how integrin adhesiveness is regulated and raise the notion of the existence of a biological rheostat for lymphocyte homing. Disturbed migratory rheostat tone could account for variations in interindividual immune responses observed in patients with inflammatory bowel disease or other lymphocyte-mediated inflammatory disorders. These findings will inform future strategies to design small molecules for the treatment of a spectrum of chronic inflammatory conditions.

Authors

Ivor S. Douglas, Themistocles Dassopoulos

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Figure 1

The interaction of the 3 β-chain cation-binding sites of lymphocyte α4β7 integrin in the unliganded state and in the liganded conformation with endothelial cell MAdCAM-1.

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The interaction of the 3 β-chain cation-binding sites of lymphocyte α4β7...
Inside-out signaling coordinates cation-dependent allosteric conformational activation of the α4β7 integrin with the transition from a low-affinity binding state to an “open-hinge,” high-affinity binding state. This facilitates MAdCAM-1 binding and firm adhesion to α4β7. The orientation in the MAdCAM-1–liganded form of the linear cluster of 3 metal-binding sites (ligand-induced metal-binding site [LIMBS], metal ion–dependent adhesion site [MIDAS], and ADMIDAS) in the ligand-binding head region of the integrin β subunit von Willebrand factor type A (βA or I-like) domain are shown in green, red, and yellow, respectively. ADMIDAS and ligand-induced metal-binding site are regulators of adhesion and de-adhesion and contribute to adhesive rheo-tone. As reported by Park et al. (5) in this issue of the JCI, ADMIDAS regulates de-adhesion of the lymphocyte’s trailing edge integrins, thus facilitating transendothelial migration along chemokine gradients.