Discovery That Integrins Can Restrain Themselves (Auto-Inhibitory Mode) May Have “Profound Implications” for Inflammatory Diseases & Lead to New Treatment Approaches

As an arm of the innate immune system, white blood cells called neutrophils form the first line of defense against invading pathogens. Neutrophils spend most of their lives racing through the bloodstream, patrolling for bacteria or other foreign particles. Once they arrive at tissues besieged by infectious agents, neutrophils halt on a dime and then blast through the vessel wall to reach the inflammatory attack site. They do this by activating integrins, a class of adhesion receptors that can switch on in less than a second. Now, a paper published by La Jolla Institute for Allergy and Immunology (LJI) researchers, and collaborators, reveals an entirely unanticipated way in which neutrophil receptors grab onto a capillary wall in preparation to breach it, as well as a cute trick they use to keep cells from sticking to each other or busting through the wrong place. That work, led by LJI immunologist Klaus Ley, M.D., and published in the August 31, 2016 issue of Nature Communications, suggests a novel way that integrins could be targeted to either dampen inflammation, as in the case of autoimmune disease, or to boost immune responses against infection. The new open-access article is titled “Neutrophil Recruitment Limited by High-Affinity Bent β2 Integrin Binding Ligand in cis.” "Once neutrophils sense a site of infection behind a capillary wall, they need to get out of circulation fast. Previously, we knew they initiated that by switching on adhesion molecules to grab onto a vessel in less than a second," says Dr. Ley, a professor and Head of LJI's Division of Inflammation Biology. "In our new study we have discovered an unexpected way that these molecules change their shape to do that." Many researchers thought that integrin receptors protruding from neutrophils became adherent via a "switchblade" mechanism.
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