Non-identical twins: Different faces of CR3 and CR4 in myeloid and lymphoid cells of mice and men

Abstract

Integrins are cell membrane receptors that are involved in essential physiological and serious pathological processes. Their main role is to ensure a closely regulated link between the extracellular matrix and the intracellular cytoskeletal network enabling cells to react to environmental stimuli. Complement receptor type 3 (CR3, αMβ, CD11b/CD18) and type 4 (CR4, αXβ, CD11c/CD18) are members of the β-integrin family expressed on most white blood cells. Both receptors bind multiple ligands like iC3b, ICAM, fibrinogen or LPS. β-integrins are accepted to play important roles in cellular adhesion, migration, phagocytosis, ECM rearrangement and inflammation. Several pathological conditions are linked to the impaired functions of these receptors. CR3 and CR4 are generally thought to mediate overlapping functions in monocytes, macrophages and dendritic cells, therefore the potential distinctive role of these receptors has not been investigated so far in satisfactory details. Lately it has become clear that a functional segregation has evolved between the two receptors regarding phagocytosis, cellular adhesion and podosome formation. In addition to their tasks on myeloid cells, the expression and function of CR3 and CR4 on lymphocytes have also gained interest recently. The picture is further complicated by the fact that while these β-integrins are expressed by immune cells both in mice and humans, there are significant differences in their expression level, functions and the pathological consequences of genetic defects. Here we aim to summarize our current knowledge on CR3 and CR4 and highlight the functional differences between these receptors, involving their expression in myeloid and lymphoid cells of both men and mice.

Critical role of integrin CD11c in splenic dendritic cell capture of missing-self CD47 cells to induce adaptive immunity

“…The inability of CD11c-or Talin1-deficient DCs to capture Even though several molecules have been shown to contain affinity for CD11c, none have been functionally verified in an in vivo setting, and the identity of the stimulatory ligand for CD11c on CD47-deficient cells is unclear. The fact that CD11b can partially compensate for CD47-deficient cell capture in the absence of CD11c suggests this potential ligand is likely shared by CD11b and CD11c, in accord with the sequence similarity of these integrin α-chains (20). Recently, the role for CD11b in phagocytosis of CD47-deficient cells has been established in BMderived macrophages.…”

“…However, Cd47 −/− RBC uptake was unaffected in macrophages lacking SLAMF7, suggesting that SLAMF7 is not the dominant ligand on Cd47 −/− RBCs (27). Another wellestablished common ligand for CD11b and CD11c is the iC3b fragment of complement C3 (17,20,28). However, DCIR2 + DC capture of Cd47 −/− RBCs and SRBCs, as well as DC activation, happens readily in C3-deficient recipients (SI Appendix, Fig.…”

“…S4B). In this regard, CD11b is 66% identical (77% homologous) to CD11c over the β-propeller and ligand-binding I domains, and these integrins share a number of ligands, including ICAM1, iC3b, fibronectin, and fibrinogen (20). Indeed, while DCs lacking CD11b (Itgam −/− ) alone showed normal RBC uptake, blocking CD11c in Itgam −/− mice led to a more profound defect in Cd47 −/− RBC capture (Fig.…”

“…CD11c pairs with Itgb2, and this integrin heterodimer has been shown to bind complement fragment iC3b and mediate phagocytosis in vitro, for which it is also referred to as complement receptor 4 (17,18). It has also been found to interact with other soluble molecules, such as heparin and fibrinogen, and with adhesion molecules such as ICAM-1 (19,20). However, the function of this prominent marker protein in DCs, especially in vivo, remains poorly defined.…”

Different Calcium and Src Family Kinase Signaling in Mac-1 Dependent Phagocytosis and Extracellular Vesicle Generation

“…The most effective opsonins are immunoglobulins reacting with different Fc receptors (FcR) and complement fragments recognized by complement receptors (CR). The most abundant CR on the surface of neutrophils is CR3, also known as macrophage antigen 1 (Mac-1), a β 2 integrin (1). In addition to phagocytosis, Mac-1 is involved in adhesion and spreading of the cells as well as in adhesion-dependent superoxide production and degranulation (2)(3)(4).…”