Leukocyte integrins: Role in leukocyte recruitment and as therapeutic targets in inflammatory disease

Abstract

Infection or sterile inflammation triggers site-specific attraction of leukocytes. Leukocyte recruitment is a process comprising several steps orchestrated by adhesion molecules, chemokines, cytokines and endogenous regulatory molecules. Distinct adhesive interactions between endothelial cells and leukocytes and signalling mechanisms contribute to the temporal and spatial fine-tuning of the leukocyte adhesion cascade. Central players in the leukocyte adhesion cascade include the leukocyte adhesion receptors of the β2-integrin family, such as the αLβ2 and αMβ2 integrins, or of the β1-integrin family, such as the α4β1- integrin. Given the central involvement of leukocyte recruitment in different inflammatory and autoimmune diseases, the leukocyte adhesion cascade in general, and leukocyte integrins in particular, represent key therapeutic targets. In this context, the present review focuses on the role of leukocyte integrins in the leukocyte adhesion cascade. Experimental evidence that has implicated leukocyte integrins as targets in animal models of inflammatory disorders, such as experimental autoimmune encephalomyelitis, psoriasis, inflammatory bone loss and inflammatory bowel disease as well as preclinical and clinical therapeutic applications of antibodies that target leukocyte integrins in various inflammatory disorders are presented. Finally, we review recent findings on endogenous inhibitors that modify leukocyte integrin function, which could emerge as promising therapeutic targets.

α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy

“…21 We have previously shown that monocyte traffic to the DRG is associated with severe DRG pathology, as well as a loss of intraepidermal nerve fiber density. 2 Herein, we used natalizumab to determine the effect of blocking leukocyte traffic on DRG pathology.…”

The Rap1-RIAM-talin axis of integrin activation and blood cell function

“…Due to their critical role in leukocyte recruitment, leukocyte integrins have emerged as potential therapeutic targets in several inflammatory diseases, and some antileukocyte integrin therapeutics have reached the clinic. 118,119 Similarly, the essential role of aIIbb3 in platelet aggregation and thrombus formation has led to aIIbb3 antagonists used to treat cardiovascular diseases. 7,119 That said, mechanism-based toxicities, ascribable to the effects of complete blockade of integrins, have limited the utility of such therapies.…”

“…114,115 Additional work is required to determine whether inhibiting RIAM can ameliorate diseases that depend on leukocyte integrin functions, eg, psoriasis and inflammatory bowel disease. 118,119 Because RIAM-deficient mice are viable, fertile, and healthy, [113][114][115] amelioration of disease models would portend a potential therapeutic benefit in blocking RIAM or the signaling events that enable its functions. Reverse genetic experiments (mutating a gene and analyzing resulting phenotype) in mice revealed that RIAM is dispensable for platelet function and associated with mild neutrophil and lymphocyte function defects.…”

“…7,119 That said, mechanism-based toxicities, ascribable to the effects of complete blockade of integrins, have limited the utility of such therapies. 7,118,119 Although much has been learned about how talin and kindlins enable integrin functions, there is a need to decipher the sequence of signal transduction events from adhesive stimuli to talin and kindlin recruitment to integrins. The function of Rap proteins as hubs in integrin inside-out signaling is widely accepted, but their connection with talin remains incompletely characterized.…”

Membrane microparticles: shedding new light into cancer cell communication

“…It is a leukocyte adhesion receptor of the β2-integrin family, which consists of major players in the leukocyte adhesion cascade (Mitroulis et al 2015). Although normally expressed only in neutrophils and monocytes, Mac-1 has been found to play an important role in MP-driven metastasis of murine hepatocarcinoma cells (Ma et al 2013).…”