Integrins in Health and Disease-Suitable Targets for Treatment?

Abstract

Integrin receptors are heterodimeric surface receptors that play multiple roles regarding cell-cell communication, signaling, and migration. The four members of the β₂ integrin subfamily are composed of an alternative α (CD11a-d) subunit, which determines the specific receptor properties, and a constant β (CD18) subunit. This review aims to present insight into the multiple immunological roles of integrin receptors, with a focus on β₂ integrins that are specifically expressed by leukocytes. The pathophysiological role of β₂ integrins is confirmed by the drastic phenotype of patients suffering from leukocyte adhesion deficiencies, most often resulting in severe recurrent infections and, at the same time, a predisposition for autoimmune diseases. So far, studies on the role of β₂ integrins in vivo employed mice with a constitutive knockout of all β₂ integrins or either family member, respectively, which complicated the differentiation between the direct and indirect effects of β₂ integrin deficiency for distinct cell types. The recent generation and characterization of transgenic mice with a cell-type-specific knockdown of β₂ integrins by our group has enabled the dissection of cell-specific roles of β₂ integrins. Further, integrin receptors have been recognized as target receptors for the treatment of inflammatory diseases as well as tumor therapy. However, whereas both agonistic and antagonistic agents yielded beneficial effects in animal models, the success of clinical trials was limited in most cases and was associated with unwanted side effects. This unfavorable outcome is most probably related to the systemic effects of the used compounds on all leukocytes, thereby emphasizing the need to develop formulations that target distinct types of leukocytes to modulate β₂ integrin activity for therapeutic applications.

Keywords: LAD-1; LFA-1; MAC-1; NETosis; leukocyte receptors; migration; phagocytosis; reactive oxygen species; αβ integrins; β2 integrins.

Figure 1

Classification and expression pattern of the αβ integrin receptor family. Integrin heterodimers consist of different combinations of the α and β subunits. In general, integrins are classified by their ligand specificity in RGD-recognizing integrins (α₅β₁, α_Vβ₁, α_Vβ₃, α_Vβ₅, α_Vβ₆, α_Vβ₈, and α_llbβ₃) shown in green, laminin-binding integrins (α₃β₁, α₆β₁, α₇β₁, and α₆β₄) shown in red, collagen-binding integrins (α₁β₁, α₂β₁, α₁₀β₁, and α₁₁β₁) shown in blue, and leukocyte integrins (α₉β₁, α₄β₁, α_Eβ₇, α_Lβ₂, α_Mβ₂, α_Xβ₂, and α_Dβ₂) shown in yellow. The β₁, β_2, and αV containing integrins built the largest groups of the family. All integrins are expressed by a wide range of cells, including, for example, leukocytes, epithelial cells, and fibroblasts. Created with BioRender.com.

Figure 2

The β₂ integrin receptor subfamily and their ligands. The common β₂ integrin subunit (CD18) can pair with one of four α subunits (α_L-CD11a, α_M-CD11b, α_X-CD11c, and α_D-CD11d), forming LFA-1, MAC-1, complement receptor 4 (150.95/CR4), and CD18/CD11d, respectively. LFA-1 is the only β₂ integrin expressed on T cells, while CD11b/CD18, CD11c/CD18, and CD11d/CD18 are also expressed on myeloid cells. β₂ integrins can interact with a wide range of ligands, including cell surface receptors, extracellular matrix ligands, plasma, and microbial ligands. Created with BioRender.com.

Figure 3

Structure of LFA-1 and conformational changes during integrin activation. (A) LFA-1 can be divided into three domains: an extracellular domain with a headpiece and tailpiece, a transmembrane, and cytoplasmic domain. (B) LFA-1 undergoes three conformational changes from bent-closed (low ICAM affinity) toward extended-closed with intermediate ICAM affinity state toward extended-open with high ICAM affinity. Upon ligand binding, the headpiece swings out of the hybrid domain with intermediate affinity. The extension between the thigh and calf-1 domain of the α subunit and the hybrid and EGF1–2 of the β domain (shown in red) results in the extended-one conformation with high ligand affinity. PSI, plexin–semaphorin–integrin. Created with BioRender.com.

Figure 4

Triggering bidirectional inside-out and outside-in signals of LFA-1. (A) Inside-out signaling is triggered, e.g., by chemokine/cytokine signaling and TCR stimulation from within the cell, resulting in LFA-1 activation. Outside-in signaling is induced by ligand binding such as ICAM-1 as well as interferon-stimulated gene 15 and divalent cations (Mg²⁺, Mn²⁺). (B) Inside-out signaling through chemokine or TCR stimulation recruits Rap1-GTP. RAPL engages CD11a and activates Rap-1. RIAM engages Rap-1 and the β subunit. The β subunit binds talin-1 and kindlin-3, stabilizing the intermediate- and high-affinity states. Additional binding of paxillin and vinculin forms a frame for interaction with cytoskeletal elements. Outside-in signaling activates adapter proteins such as talin-1, which mediate downstream signaling and mechanotransduction. Created with BioRender.com.

Figure 5

Role of LFA-1-mediated contact for T_H17/iTreg polarization. LFA-1 triggers STAT3 activation and interrupts TGF-β signaling. LFA-1 triggered STAT3 activation by phosphorylation (P), translocating STAT3 to the nucleus, and its interaction with stathmin and Rho GTPase controls microtubule dynamics. In the nucleus, STAT3 upregulates the expression of the TGF-β-inhibiting transcription factors SMAD7, SMURF2, SKI, and SKIL. These proteins hinder TGF-β-mediated inhibition of IL-2 secretion and T-cell differentiation into T_H17 or iTreg cells. Created with BioRender.com.

Figure 6

Leukocyte adhesion deficiency syndromes. The trafficking of leukocytes is a multistep process, including rolling along endothelia, adhesion, arrest, crawling, and finally, extravasation. LAD-1 syndrome is characterized by decreased or absent β2 integrin expression, resulting in impairment of leukocyte firm adhesion and migration into tissue. LAD-2 patients have a deficiency in selectin ligand expression, resulting in insufficient rolling of leukocytes. Humans with LAD-3 syndrome have no functional kindlin-3, which is an important adaptor protein for correct integrin activation. β1, β2, and β3 integrins cannot switch to their high-affinity state and interact with their ligands. Consequently, leukocytes are not able to adhere to the endothelium. Created with BioRender.com.