M. Amin Arnaout, MD
A major research focus of my laboratory is the dissection of the role of leukocyte integrins in inflammation, and an elucidation of the mechanisms that regulate the functions of these adhesion receptors in health and disease. Leukocyte integrins play pivotal roles in mediating the extravasation and homing of leukocytes under normal conditions, as part of immunosurveillance and host defense. The improper production/release of inflammatory mediators can change the kinetics of extravasation and/or misdirect normal homing, leading to the initiation and/or propagation of tissue injury that underlies many diseases including stroke, heart attacks and autoimmune disorders. The proinflammatory profile that exists in diabetes mellitus for example is multifactorial, but includes upregulation of integrins and modifications of the endothelial cell phenotype favoring pathologic adhesion to leukocytes. In this pathologic condition, leukocyte integrins switch from low to high affinity states leading to tissue injury.
The dynamic nature of integrin-mediated cell migration necessitates that these receptors be able to rapidly and reversibly alter their affinity to ligands. The basic mechanisms that underlie affinity switching in integrins are poorly understood both at a cell signaling level as well as at a structural level. Deletions of integrin cytoplasmic tails alter the affinity state of integrins, suggesting that intracellular interactions are directly involved in modulating extracellular integrin-ligand interactions. In addition, ligation of integrins by ligands elicits downstream signaling events that regulate cell growth, differentiation, motility and fate. The nature of these inside-out and outside-in signals remains obscure. Using genetic, molecular and structural biology approaches, our goal is to define the structural basis of affinity switching in integrins, elucidate the intracellular pathways that regulate these receptors and that mediate their downstream effects, and use this information in designing novel anti-inflammation therapeutics.