The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology

Abstract

The β2-integrin receptor family has a broad spectrum of physiological functions ranging from leukocyte adhesion, cell migration, activation, and communication to the phagocytic uptake of cells and particles. Among the members of this family, complement receptor 3 (CR3; CD11b/CD18, Mac-1, αMβ2) is particularly promiscuous in its functional profile and ligand selectivity. There are close to 100 reported structurally unrelated ligands for CR3, and while many ligands appear to cluster at the αMI domain, molecular details about binding modes remain largely elusive. The versatility of CR3 is reflected in its functional portfolio, which includes prominent roles in the removal of invaders and cell debris, induction of tolerance and synaptic pruning, and involvement in the pathogenesis of numerous autoimmune and chronic inflammatory pathologies. While CR3 is an interesting therapeutic target for immune modulation due to these known pathophysiological associations, drug development efforts are limited by concerns of potential interference with host defense functions and, most importantly, an insufficient molecular understanding of the interplay between ligand binding and functional impact. Here, we provide a systematic summary of the various interaction partners of CR3 with a focus on binding mechanisms and functional implications. We also discuss the roles of CR3 as an immune receptor in health and disease, as an activation marker in research and diagnostics, and as a therapeutic target.

Structural insights into the function-modulating effects of nanobody binding to the integrin receptor αMβ2

“…The examples of aforementioned α M β 2 -linked diseases demonstrate that pharmacological regulation of α M β 2 activity is clinically relevant. The complications with respect to therapeutic modulation of the receptor and the repertoire of natural and man-made molecules targeting α M β 2 has recently been extensively reviewed ( 51 ). Currently, the most advanced drug candidate is the α M β 2 agonist leukadherin-1 (LA-1), a small molecule that stimulates leukocyte α M β 2 interaction with ICAM-1 and iC3b-presenting cells ( 52 ).…”

“…Animal experiments could investigate the in vivo utility of properly modified hCD11bNb1 as a highly specific α M β 2 agonist, but such studies are complicated by the lack of crossreactivity with the murine αI domain. Another major complication with respect to the in vivo effects of our Nb is the large number of proteins reported to interact with the αI domain besides iC3b ( 51 ), with ICAM-1, fibrinogen, RAGE, JAM-C, and glycoprotein bα as prominent examples. For other ligands, steric hindrance exerted by hCD11bNb1 could be larger than for the C3d/iC3b–αI interactions investigated here.…”

Molecular Genetics and Cytotoxic Responses to Titanium Diboride and Zinc Borate Nanoparticles on Cultured Human Primary Alveolar Epithelial Cells

“…In the last decade, nanotechnology has been utilized in many different fields from industrial applications to food and health applications. Recently, boron-based nano-compound integrations into various technologies have begun to be discussed in many studies because of their superior and versatile properties [ 20 , 21 , 22 , 23 ]. Studies have claimed that inhalation is the most common route for NPs exposure and molecules are transferred from the upper respiratory tract to bronchioles by electrostatic force of the air.…”

RAGE pathway activation and function in chronic kidney disease and COVID-19

“…Mac-1, a leukocyte integrin (CD11b/CD18, α M β 2 -integrin, CR3), binds soluble ligands (e.g., fibrinogen, factor X, and complement factor iC3b) and cell surface receptors (e.g., CD40L, ICAM-1, platelet GPIbα, and RAGE) to regulate cell signaling, adhesion/extravasation, phagocytosis, thrombosis, and inflammation ( 115 ). Heparin also binds Mac-1 and tends to impede the binding of soluble and cell surface ligands to Mac-1 ( 116 ).…”