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

The ß2-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, αMß2) 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.

A Human Three-Dimensional In Vitro Model of Lens Epithelial Cells as a Model to Study Mechanisms of Drug-Induced Posterior Subcapsular Cataracts.

Purpose: Cataract is a pathological opacification of the lens, which is still one of the leading causes of blindness in the world. Several etiologies are described, among them drug-induced cataract, for example, posterior subcapsular cataract (PSC) after steroid treatment. To investigate different mechanisms of drug-induced cataract a human three-dimensional (3D) lens in vitro model was developed, consisting of immortalized human lens epithelial cells. Methods: These cells were cultivated on 96-well, ultralow attachment plates, where they rapidly form spheroids. By gene expression analysis different markers were observed, which are important to maintain lens transparency, such as ephrin type-A receptor 2 (EphA2) or α-smooth muscle actin (α-SMA). Results: The lens epithelial cells form a spheroid within a few days and show stable expression of important lens marker, and size and viability remain stable up to 26 days in culture. The gene expression of the glucocorticoid-treated spheroids revealed a clear shift in the expression of EphA2, α-SMA, αB-crystallin (CRYAB), and heat shock protein beta-1 (HSPB1). Furthermore, the glucocorticoid treatment did not improve cell survival. Conclusions: This study proposes a useful 3D in vitro model, which expresses important lens markers and is capable of demonstrating features found in drug-induced cataracts. As the viability remains stable over long time, this model can also be used for long-term treatment. The main characteristics are the increased expression of α-SMA, CRYAB, and HSPB1 and the decreased expression of EphA2. The present data provide some first evidence on novel mechanisms involved in glucocorticoid-induced cataracts.