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, α_Mβ₂) 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 α_MI 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.

Keywords: CR3 (CD11b/CD18); autoimmune diseases; complement; host defense; inflammation; integrin.

Figure 1

Structure and function of CR3. CR3 exerts a broad variety of functions in host-defense and leukocyte motility. Some of them are shown.

Figure 2

Integrins remain in a low affinity, bent-closed state. Cytoplasmic factors such as talin and kindlin connect the cytoplasmic tail of the integrins to the cytoskeleton. This leads to an extension of the extracellular domains with an open, high affinity, ligand accessible headpiece. CR3 is able to bind to protein on the same surface, which is termed cis-ligation/cis-interaction.

Figure 3

Overview over reported competing/not competing CR3 ligands. Competing ligands are marked in blue, not competing ligands are marked in salmon.

Figure 4

α_MI domain (pdb: 1IDO) as cartoon and surface shown as mesh, Mg²⁺ in red. Binding sites of ligands reported by mutational, competition, structural or docking studies: (A) iC3b (green), C3d (yellow), (B) NIF (pink), LukGH (orange), (yellow for overlapping), (C) glucosamine (blue), FCgRII (orange), and CD40L and LRP1 (cyan), (D) GPIbα (ruby), fibrinogen (green).

Figure 5

Overview of important antibodies developed against CD11b and CD18 mapped to their reactive regions.

Figure 6

Small molecules developed as possible CR3 modulators.