The role of integrins in inflammation and angiogenesis

Abstract

Integrins are heterodimeric transmembrane cell adhesion molecules made up of alpha (α) and beta (β) subunits arranged in numerous dimeric pairings. These complexes have varying affinities to extracellular ligands. Integrins regulate cellular growth, proliferation, migration, signaling, and cytokine activation and release and thereby play important roles in cell proliferation and migration, apoptosis, tissue repair, as well as in all processes critical to inflammation, infection, and angiogenesis. This review presents current evidence from human and animal studies on integrin structure and molecular signaling, with particular emphasis on signal transduction in infants. We have included evidence from our own laboratory studies and from an extensive literature search in databases PubMed, EMBASE, Scopus, and the electronic archives of abstracts presented at the annual meetings of the Pediatric Academic Societies. To avoid bias in identification of existing studies, key words were short-listed prior to the actual search both from anecdotal experience and from PubMed's Medical Subject Heading (MeSH) thesaurus. IMPACT: Integrins are a family of ubiquitous αβ heterodimeric receptors that interact with numerous ligands in physiology and disease. Integrins play a key role in cell proliferation, tissue repair, inflammation, infection, and angiogenesis. This review summarizes current evidence from human and animal studies on integrin structure and molecular signaling and promising role in diseases of inflammation, infection, and angiogenesis in infants. This review shows that integrin receptors and ligands are novel therapeutic targets of clinical interest and hold promise as novel therapeutic targets in the management of several neonatal diseases.

Fig. 1. Classification of integrin family.

Integrin heterodimers consists of numerous combinations of α and β subunits. With respect to ligand specificity, integrins are generally classified as collagen-binding integrins (α₁β₁, α₂β₁, α₁₀β₁, and α₁₁β₁), RGD-recognizing integrins (α₅β₁, α_Vβ₁, α_Vβ₃, α_Vβ₅, α_Vβ₆, α_Vβ₈, and α_IIbβ₃), laminin-binding integrins (α₃β₁, α₆β₁, α₇β₁, and α₆β₄), and leukocyte integrins (α_Lβ₂, α_Mβ₂, α_Xβ₂, and α_Dβ₂). The β₂ integrin subunit (CD18) can pair with one of the four α subunits (α_L-CD11a, α_M-CD11b, α_X-CD11c, and α_D-CD11d), forming leukocyte function-associated antigen-1, Mac1/CR3 (macrophage-1 antigen, complement receptor 3), 150.95/CR4 (complement receptor 4), and CD18/CD11d, respectively. CD11a/CD18 is expressed mainly on all leukocytes, while CD11b/CD18, CD11c/CD18, and CD11d/CD18 are expressed on myeloid cells.^, The α_Mβ₂ integrin (also known as CR3, CD11b/CD18, or Mac-1) is found on phagocytic cells and implicated in the adhesion of leucocytes to endothelium and opsonization of microbes. Ligands for CR3 include the complement component iC3b, the intercellular adhesion molecule (1CAM-1), and coagulation factors like fibrinogen and factor X.

Fig. 2. Schematic of integrin structure and activation.

Structurally, the αβ integrin subunits are type 1 transmembrane proteins. Each subunit consists of one large multi-domain extracellular segment, one transmembrane helix, and a short cytoplasmic tail. The extracellular region interacts with ECM ligands and is composed of about 1104 (700–1100) residues in the α subunit and 778 residues in the β subunits and shorter cytoplasmic domains with 30–50 residues. The short cytoplasmic tails are composed of 20–70 amino acids and mediate interactions with intracellular cytoskeletal and signaling proteins. In response to intracellular or extracellular stimuli, integrin activation occurs by ligand binding or by the changes on the cytoplasmic domains, resulting in elongation and separation of the legs. Integrins appear in a closed or “bent” conformation on resting cells and display a low binding affinity for ligand rendering them inactive to ligand binding or signal transduction; while once activated, the integrin shape extends to an open conformation leading to a high affinity. In a closed conformation, integrins show low ligand-binding affinity, partly due to the bend in the center of the α and β subunits, which brings the ligand-binding site within 5 nm of the cell surface. However, when the conformation is open, the two subunits straighten with increased integrin affinity for the ligand. The initial binding of extracellular ligand effects separation of the cytoplasmic domains, allowing interaction with signal transduction and cytoskeletal molecules during outside-in signaling, while separation of the cytoplasmic domains by talin and other activators activates the head to enable ligand binding during inside-out signaling.

Fig. 3. Schematic of integrin regulation of angiogenic signaling.

The schematic shows the interaction between the signaling pathways regulated by αβ integrins and the VEGF receptor. VEGF-A promotes angiogenesis through VEGF receptor-2 (VEGFR2), a tyrosine kinase receptor expressed by endothelial cells. When VEGF-A binds to VEGFR2, numerous intracellular signaling pathways are activated, such as phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (Erk), focal adhesion kinase (FAK), c-Src family, and paxillin, a signal transduction adaptor protein associated with focal adhesion.^, Specifically, FAK phosphorylates its substrate, paxillin, which activates ERK signaling. When integrins activate the tyrosine phosphorylation of FAK, it binds to signaling structural proteins, PI3K, and paxillin. Src family kinases (SFKs) play a critical role in cell adhesion, survival, and angiogenesis, interact with VEGF receptor, regulate gene expression of angiogenic growth factors, modulate cell proliferation via the mitogen-activated protein kinases (MAPK)-ERK pathway, and interact with integrins to regulate cell adhesion and migration. ECM extracellular matrix, VEGF vascular endothelial growth factor.