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Non-Identical Twins: Different Faces of CR3 and CR4 in Myeloid and Lymphoid Cells of Mice and Men Anna Erdeia B, Szilvia Lukács

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Non-Identical Twins: Different Faces of CR3 and CR4 in Myeloid and Lymphoid Cells of Mice and Men Anna Erdeia B, Szilvia Lukács Non-identical twins: Different faces of CR3 and CR4 in myeloid and lymphoid cells of mice and men Anna Erdei a b, Szilvia Lukácsi a b , Bernadett Mácsik-Valent a b, Zsuzsa Nagy-Baló b, István Kurucz a, Zsuzsa Bajtay ab a MTA-ELTE Immunology Research Group, Department of Immunology, Eötvös Loránd University, Budapest, Hungary b Department of Immunology, Eötvös Loránd University, Budapest, Hungary * Corresponding author Anna Erdei Department of Immunology, Eötvös Loránd University, Pázmány Péter s. 1/C, Budapest H-1117, Hungary Phone: (+36)-1-3812-175 Fax: (+36)-1-3812-176 e-mail: [email protected], [email protected] 1 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, αMβ2, CD11b/CD18) and type 4 (CR4, αXβ2, CD11c/CD18) are members of the β2-integrin family expressed on most white blood cells. Both receptors bind multiple ligands like iC3b, ICAM, fibrinogen or LPS. β2- 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 β2-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. Keywords:CR3, CR4, β2integrins, human, mouse 1. Introduction The name “integrin” was given to point out that these integral cell membrane proteins ensure and maintain the integrity of the cytoskeletal-extracellular matrix (ECM) linkage [1]. Integrins are cell adhesion molecules that mediate cell-cell, cell-extracellular matrix, and cell- pathogen interactions. They play critical roles in several immune phenomena where leukocyte trafficking and migration are involved, immunological synapses are formed, costimulation and phagocytosis take place. These hetero-dimeric glycoproteins consist of non-covalently coupled α and β chains. Integrins are ancestral receptors with early evolutional history, since both the α- and β- subunits can be found throughout the invertebrates from nematodes and fruit flies with remarkably well conserved sequences [2]. The integrin α and β subunits have 2 developed separately during evolution. In vertebrates, the molecules of the integrin family are composed of 18 α and 8 β subunits, that can assemble into 24 different heterodimeric receptors, each with different ligand-binding specificities and a diverse tissue distribution [3]. In mammals, nine of the 18 α subunits have the “inserted” or “αI” domain, forming the ligand recognition part of the receptor. Four αI domain containing integrins are collagen receptors, while the other five recognize E-cadherins, ICAMs or VCAMs and two of them (CR3, CR4) also bind plasma proteins such as fibrinogen, FactorX or component iC3b [4]. Both subunits, namely the α and the β chain have a large extracellular ligand binding region, a single transmembrane domain and a short cytoplasmic tail (Figure 1.). Recently the interest has been revived in the physiological and pathological role of CR3 and CR4, members of the β2-integrin family. Therefore we aim to give an overview on the structure, expression and diverse functions of these complement receptors on myeloid as well as lymphoid cells, suggesting a „division of labour” regarding their distinct roles on phagocytes. We also aim to highlight similarities and differences between the human and murine systems. 2. Complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) Complement receptor type 3 (CR3) and type 4 (CR4) belong to the β2-integrin family (Figure 1.). As it will be discussed later in detail, they are expressed on all myeloid cells and certain lymphoid populations. The members of this family differ in their specificity and avidity to the different ligands. Associated with the common β2 chain (CD18) the four members of this family are the following: αLβ2 integrin (also known as LFA-1 or CD11a/CD18), αMβ2 integrin (Macrophage antigen-1 (Mac-1), complement receptor 3 (CR3 or CD11b/CD18), αXβ2 integrin (p150,95, CD11c/CD18 or complement receptor 4 (CR4)), and αDβ2 integrin (CD11d/CD18) [5, 6]. Among the complement receptors binding various C3-fragments CR3 and CR4 have the unique property that their ligand binding is metal-ion dependent. CD11c is closely related to CD11b. It is 66% identical and 77% homologous to Mac-1 over the β-propeller and the ligand-binding I domains. They bind similar ligands, including iC3b, ICAM and fibrinogen [7-10] via the metal-ion-dependent adhesion site (MIDAS) in the presence of a bivalent cation [11]. Sequence analysis of human cDNA encoding the α chains of CR3 and CR4 (165 and 150 kD Mw) show a homology of 87% [12, 13], however these two integrins bind iC3b at distinct sites [14]. A greater structural difference is present in the cytoplasmic domains of 3 CR3 and CR4 α chains. The cytoplasmic tail of CR3 α (CD11b) has only 56% homology with the cytoplasmic domain of CR4 α (CD11c), and is less than two-third of its size. This suggests that functional differences between CR3 and CR4 may be derived from differences in their ability to associate with cytoplasmic components such as signalling or actin-binding proteins [13]. The common β-subunit extracellularly has an N-terminal I-like domain, a sandwich hybrid domain, a cysteine-rich PSI (plexin-semaphorin-integrin) domain, four EGF-like repeats (I-EGF1, -2, -3, -4) and a β-tail domain (βTD) (Figure 1.). CR3 and CR4 are named complement receptors as they readily interact with the iC3b fragment of the major component C3, generated during activation of the complement cascade (Figure 2.). However, as indicated in the figure these receptors interact with several additional structures, including ICAMs, the cell surface adhesion molecules, fibronectin, the adhesion molecule in extracellular matrix, and fibrinogen, the coagulation factor. The most studied functions of these receptors are phagocytosis, adherence and podosome formation. The earliest investigations identified CD11b/CD18 as a phagocytic β2-integrin specific to iC3b opsonized antigen, which was identical with the Mac-1 antigen expressed by mouse and human myeloid cells as well [13, 15]. While the main role of CR3 is to promote phagocytosis and cytotoxicity, it is also known to enhance the function of several effector molecules such as FcγR, uPAR, and CD14 [16]. It was demonstrated that association of macrophage cytoskeleton with CR3 and CR4 regulates receptor mobility and phagocytosis of iC3b-opsonized erythrocytes [13]. The α chain of CR4, CD11c is a cell surface marker which can be used to identify human myeloid cell subsets. 3. Expression of CR3 and CR4 Both CR3 and CR4 are widely expressed on most of the myeloid and lymphoid cell types both in men and mice, although the extent of their appearance varies. These receptors are usually upregulated on activated cells, irrespective of their naive expression status. In Table 1. we summarize available data and indicate the presence of these β2-family integrins using the plus/minus sign. Table 1. Expression of CR3 and CR4 on human and mouse myeloid and lymphoid cells. 4 HUMAN MOUSE CR3 CR4 CR3 CR4 MYELOID CELLS Monocyte + [17, 18] + [17, 18] + [19, 20] +/- [20, 21] Macrophage +++ [17, 22] +++ [17, 22] + [23] +/- [23-25] Dendritic cell +++ [17, 26] +++ [17, 26] +/- [27, 28] +++ [24, 29] Neutrophil + [18, 30] + [18] + [31] +/- [32] LYMPHOID CELLS NK cell ++ [33, 34] +/- [35] +/- [20, 36] +/- [37] T cell +/-* [33, 38] +/-* [18, 39] +/-* [40, 41] +/-* [40, 42-45] B cell +/-* [33, 46-48] +/-* [46, 47, 49, 50] +/- [50, 51] +/- [50, 52] +/- appears on certain subpopulations +/-* appears on activated and leukemic cells 3.1. Expression of CR3 and CR4 on human myeloid cells These integrins can be found on all myeloid cells, namely neutrophil granulocytes, monocytes, macrophages and dendritic cells [17, 18, 30]. An important progress has been made recently, when the absolute number of these receptors has been assessed on human monocytes, monocyte-derived macrophages (MDM), monocyte-derived dendritic cells (MDDC) [17] and neutrophils (Table 2.). Data shown reveals that the expression level of the two receptors varies between cell types. Comparing the relative number of CR3 and CR4 on the same cell types there is a strong shift in favour of CR3 in the case of monocytes and neutrophils, whereas on MDMs and MDDCs the CD11b:CD11c ratio is close to 1:1. The 5 notable differences in receptor number most probably contribute to the functional diversity observed in the case of these cell types. Furthermore, the availability of ligand epitopes may also influence the competition between these receptors, determining the outcome of the interactions. Table 2. The average number of CR3 and CR4 expressed by normal human myeloid cells (receptor number x103 /cell) Monocytes MDM MDDC PMN* CR3 (CD11b/CD18) 50±8 310±62 247±21 47±6 CR4 (CD11c/CD18) 7±3 185±40 204±25 3,5±2 Ratio of 7,1 1,7 1,2 13,4 CD11b and CD11c *Personal communication by Dr.
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