INTEGRIN FUNCTION IN LEUKOCYTE-MEDIATED INFLAMMATION-ACTINOPATHIES IN IMMUNE DISEASES

Abstract

Integrins play a critical role in leukocyte recruitment and activation within inflamed tissues. These heterodimeric cell-surface receptors recognize ligands on vascular endothelium or extracellular matrix to initiate intracellular signals leading to leukocyte adhesion, migration, and activation. The best-described role for integrins is in the leukocyte adhesion cascade, which is the process by which leukocytes exit the blood vasculature and enter the tissues in response to infection or injury. During the adhesion cascade, integrin signaling is required for changes in leukocyte cytoskeletal structure required for firm adhesion to endothelial cells, followed by intravascular crawling and transmigration from the bloodstream into the tissues. During this process, integrin signaling augments leukocytes' inflammatory and antimicrobial functions. Mutations in the genes encoding integrins or their downstream signaling molecules result in immunodeficiency and altered tissue repair following injury. Many of these mutations occur in proteins involved in the reorganization of the actin cytoskeleton and have become known as actinopathies, the classic example being Wiskott-Aldrich syndrome. We describe a new actinopathy-type mutation in the integrin signaling molecule SKAP2, which is associated with autoimmunity and type 1 diabetes.

Fig. 1.

Integrin signaling induces actin cytoskeletal rearrangement. In resting leukocytes, integrins are in an inactive or closed conformation, which blocks the ligand binding domains. External stimuli, such as chemokine binding to GPCR receptors, lead to a signaling pathway involving RAP1 and other molecules, which results in the unfolding of the integrin into an active or open conformation. This pathway is the “inside-out” signaling response. Full integrin activation to the high-affinity state is achieved by association of additional molecules, such as talin and kindlin. The high-affinity integrin then recognizes endothelial adhesion ligands (such as ICAMs or extracellular matrix proteins like fibrinogen), which then initiate a second signaling response referred to as the “outside-in” pathway. This pathway involves tyrosine kinases and actin-associated molecules, such as WASP and SKAP2, that link the integrin to the actin cytoskeleton. This allows for changes in cell shape that are needed for full adhesion, intraluminal migration, and transmigration out of the vasculature into the tissues.

Fig. 2.

Increased neutrophil superoxide production in SKAP2 G153R mutant individual. Peripheral blood neutrophils from the SKAP2 patient or parent control were plated on (A) poly-RGD peptide-coated wells, (B) pRGD in the presence of TNFα, or (C) pRGD + LPS, and ROS was monitored by luminol reduction as described (55). Note Y-axis scale differences in samples stimulated with TNFα or LPS, which activates integrin signaling (n=3 per time point, error bars = SEM, ****p <0.0001 by Kruskal–Wallis test).