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 signaling 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.

Keywords: Del-1; Efalizumab; Integrin; Leukocyte adhesion; Natalizumab; Vedolizumab.

Figure 1. The multistep model of leukocyte recruitment

The sequential steps of the leukocyte adhesion cascade and the adhesive interactions between endothelium and leukocytes are shown. The cascade is initiated with leukocyte capturing and rolling on the endothelium, followed by chemokine-induced leukocyte activation, slow rolling, firm leukocyte adhesion/arrest, adhesion strengthening induced by integrin ligation, crawling and leukocyte transmigration. Essential molecular players involved in the adhesive processes include: selectins and their glycoprotein ligands, chemokines and their receptors, integrins and adhesion receptors of the immunoglobulin-superfamily. α4- and β2-integrins play a critical role in the course of the cascade. Integrin activation occurs upon chemokine triggered signaling (inside-out signaling) in cooperation with selectin-activated pathways. Activated integrins contribute to slow rolling, firm adhesion, crawling and to transendothelial migration.

Figure 2. Leukocyte integrin targeting in animal inflammatory models

The role of the β2 integrins αMβ2 and αLβ2 has been studied in several animal models of inflammatory disorders. In autoimmune encephalomyelitis (EAE), a rodent model resembling multiple sclerosis, either treatment with an antibody against CD11b or CD11a or deficiency in one of these integrins leads to reduced EAE disease severity. Administration of anti-CD11b or anti-LFA-1 antibodies limits skin manifestations and inflammation in psoriatic models. In addition, deficiency in the β2 subunit CD18 protects animals from arthritis development and combined inhibition of CD11b and CD11a leads to significantly decreased neutrophil recruitment. CD11a blockade has also been linked to decreased bone loss in inflammatory arthritis models, whereas mice lacking CD11a demonstrate bone loss in a periodontitis model. Regarding the inflammatory bowel diseases (IBD), CD11b inhibition leads to reduced inflammatory cell infiltration and less mucosal damage in a model of colitis. In addition, β1 integins serve as targets for interevention in inflammatory disease models. Blockade of α4β1 prevents disease development in an EAE model. Furthermore, T cell recruitment to the synovium is dependent on α4β1-integrin as shown in a model of arthritis. Besides α4β1, the inhibition of α1β1-integrin has been shown to be beneficial by inhibiting disease development in a psoriatic model. In addition, α4β7 blockade attenuates T cell homing to Peyer’s patches, a main component of gut-associated lymphoid tissue (GALT). Moreover, treatment with antibodies against either αEβ7 or β7 reduces inflammation in a model of colitis.