Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease

Abstract

Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation. Intriguingly, however, they have also been found to negatively regulate cytokine responses, maturation, and migratory responses in myeloid cells such as macrophages and dendritic cells, revealing new, and unexpected roles of these molecules in immunity. Because of their essential role in leukocyte function, a lack of expression or function of beta2-integrins causes rare immunodeficiency syndromes, Leukocyte adhesion deficiency type I, and type III (LAD-I and LAD-III). LAD-I is caused by reduced or lost expression of beta2-integrins, whilst in LAD-III, beta2-integrins are expressed but dysfunctional because a major integrin cytoplasmic regulator, kindlin-3, is mutated. Interestingly, some LAD-related phenotypes such as periodontitis have recently been shown to be due to an uncontrolled inflammatory response rather than to an uncontrolled infection, as was previously thought. This review will focus on the recent advances concerning the regulation and functions of beta2-integrins in leukocyte trafficking, immune suppression, and immune deficiency disease.

Herpes Simplex Virus Type-2 Paralyzes the Function of Monocyte-Derived Dendritic Cells

“…Patients show severe recurrent infections and a defect in tissue repair. This reveals the importance of β2 integrins in immune surveillance [41][42][43][44].…”

Therapeutic targeting of neutrophil exocytosis

“…Secretory vesicle exocytosis increases plasma membrane expression of adhesion molecules such as CD11b/CD18, which mediates firm adhesion, crawling, and migration through the endothelial cell barrier . Deficiency of CD11b/CD18 expression or activity results in leukocyte adhesion deficiency, a rare inherited disorder that is associated with life‐threatening bacterial and fungal infections due to impaired neutrophil recruitment . Engagement of neutrophil adhesion receptors with selectins on endothelial cells during rolling activates a constitutively expressed integrin, CD11a/CD18, leading to neutrophil arrest .…”

“…48 Deficiency of CD11b/CD18 expression or activity results in leukocyte adhesion deficiency, a rare inherited disorder that is associated with life-threatening bacterial and fungal infections due to impaired neutrophil recruitment. 49 Engagement of neutrophil adhesion receptors with selectins on endothelial cells during rolling activates a constitutively expressed integrin, CD11a/CD18, leading to neutrophil arrest. 50 G protein-coupled receptors bind chemokines expressed on the surface of endothelial cells, leading to a conformational change required for high affinity ligand binding by CD11a/CD18.…”

The differential role of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in the adherence, migration and podosome formation of human macrophages and dendritic cells under inflammatory conditions

“…Integrins are known to mediate cell adhesion, spreading and migration through the establishment of cell-cell and cell-extracellular matrix connections [66,67]. Our group focuses on dissecting the individual roles of the β 2 -integrins CR3 and CR4, querying the assumption that they have overlapping, or even identical functions.…”