Alternative titles; symbols
HGNC Approved Gene Symbol: ITGAM
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:31,259,975-31,332,877 (from NCBI)
A major surface antigen family on human leukocytes includes complement receptor type 3 (CR3A; also called ITGAM, Mac1, or Mo1), lymphocyte function-associated (LFA) antigen type 1 (ITGAL; 153370), and p150,95 (ITGAX; 151510). These antigens share a common beta chain (ITGB2; 600065) of 94 kD, linked noncovalently to 1 of 3 alpha chains distinctive to each. They promote adhesion of granulocytes to each other and to endothelial cell monolayers. The apparent molecular weight of the Mo1 alpha chain is 155 to 165 kD, that of the LFA1 alpha subunit is 180 kD, and that of the Leu M5 subunit is 130 to 150 kD. Pierce et al. (1986) purified human Mo1 to homogeneity from normal granulocytes by affinity chromatography and high performance liquid chromatography (HPLC) and determined the N-terminal amino acid sequence of its alpha subunit. The obtained sequence was identical, except for 2 conservative substitutions, to that of the alpha subunit of Mac1 antigen (Springer et al., 1985). Furthermore, Pierce et al. (1986) found that the N-terminal amino acid sequence of the alpha subunit of Mo1 was homologous to the alpha subunit of IIb/IIIa (607759), a glycoprotein that serves similar adhesive functions on platelets and is deficient or defective in Glanzmann thrombasthenia (273800). Patients with a history of recurrent bacterial infections and an inherited deficiency of all 3 leukocyte membrane surface antigens are thought to have reduced or absent synthesis of the common beta subunit of the antigen family; see 116920.
Arnaout et al. (1988) described the isolation and analysis of 2 partial cDNA clones encoding the alpha subunit of Mo1 in humans and guinea pigs. A comparison of the coding region of the MO1A gene revealed significant homology with the carboxyl-terminal portions of the alpha subunits of fibronectin, vitronectin, and platelet IIb/IIIa receptors.
Corbi et al. (1988) described full-length cDNA clones for the alpha subunit of Mac1.
Arnaout et al. (1988) reported the complete amino acid sequence as deduced from cDNA for the human alpha subunit. The protein consists of 1,136 amino acids with a long amino-terminal extracytoplasmic domain, a 26-amino acid hydrophobic transmembrane segment, and a 19-carboxyl-terminal cytoplasmic domain. The alpha subunit is highly similar in sequence to the alpha subunit of leukocyte p150,95.
By Southern analysis of DNA from hamster-human hybrids, Arnaout et al. (1988) localized the human MO1A gene to chromosome 16, which has been shown to contain the ITGAL gene (153370). By in situ hybridization, Corbi et al. (1988) demonstrated that the genes encoding the alpha subunits of LFA1 (ITGAL), Mac1, and p150,95 (ITGAX), all of which are involved in leukocyte adhesion, constitute a cluster on 16p13.1-p11. Callen et al. (1991) narrowed the assignment to 16p11.2.
Inflammation plays an essential role in the initiation and progression of atherosclerosis. Simon et al. (2000) presented evidence that it also has a role in vascular repair after mechanical arterial injury (i.e., percutaneous transluminal coronary angioplasty, or PTCA). In animal models of vascular injury, leukocytes are recruited as a precursor to intimal thickening. Markers of leukocyte activation, in particular, increased expression of Mac1, which is responsible for firm leukocyte adhesion to platelets and fibrinogen on denuded vessels, predict restenosis after PTCA. To determine whether Mac1-mediated leukocyte recruitment is causally related to neointimal formation, Simon et al. (2000) subjected Mac1 knockout mice to a mechanical carotid artery dilation and complete endothelial denudation. They found that the selective absence of Mac1 impaired transplatelet leukocyte migration into the vessel wall, reducing leukocyte accumulation. Diminished medial leukocyte accumulation was accompanied by markedly reduced neointimal thickening after vascular injury. These data established a role for inflammation in neointimal thickening and suggested that leukocyte recruitment to mechanically injured arteries may prevent restenosis.
Ranganathan et al. (2011) noted that previous work (Cao et al., 2006) had shown colocalization of low density lipoprotein receptor-related protein-1 (LRP1; 107770) with integrin alpha-M/beta-2 at the trailing edge of migrating macrophages and that macrophage migration depended upon coordinated action of LRP1 and alpha-M/beta-2, as well as tissue plasminogen activator (PLAT; 173370) and its inhibitor, PAI1 (SERPINE1; 173360). Ranganathan et al. (2011) found that LRP1 specifically bound integrin alpha-M/beta-2, but not integrin alpha-L/beta-2. Activation of alpha-M/beta-2 by lipopolysaccharide (LPS) enhanced interaction between LRP1 and alpha-M/beta-2 in macrophages. Transfection experiments in HEK293 cells revealed that both the heavy and light chains of LRP1 contributed to alpha-M/beta-2 binding. Within the LRP1 heavy chain, binding was mediated primarily via ligand-binding motifs 2 and 4. Within alpha-M, the sequence EQLKKSKTL within the I domain was the major LRP1 recognition site. Exposure of alpha-M/beta-2-expressing HEK293 cells to soluble LRP1 inhibited cell attachment to fibrinogen (see 134820). Mouse macrophages lacking Lrp1 were deficient in alpha-M/beta-2 internalization upon LPS stimulation. Ranganathan et al. (2011) concluded that LRP1 has a role in macrophage migration and that it is critical for internalization of integrin alpha-M/beta-2.
Chen et al. (2017) found that macrophages are much more efficient at phagocytosis of hematopoietic tumor cells, compared with nonhematopoietic tumor cells, in response to SIRP-alpha (SIRPA; 602461)-CD47 (601028) blockade. Using a mouse lacking the signaling lymphocytic activation molecule (SLAM) family of homotypic hematopoietic cell-specific receptors, Chen et al. (2017) determined that phagocytosis of hematopoietic tumor cells during SIRPA-CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7, expressed on macrophages and tumor cell targets. In contrast to most SLAM receptor functions, SLAMF7-mediated phagocytosis was independent of SLAM-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin MAC1 and utilize signals involving immunoreceptor tyrosine-based activation motifs. Chen et al. (2017) concluded that their findings elucidated the mechanism by which macrophages engulf and destroy hematopoietic tumor cells, and revealed a novel SAP adaptor-independent function for a SLAM receptor.
For discussion of a possible association between variation in the ITGAM gene and systemic lupus erythematosus, see SLEB6 (609939).
Martinez et al. (2020) generated knockin mice expressing Cd11b with an ile332-to-gly (I332G) that resulted in constitutively active Cd11b with a higher affinity for its ligand. Mutant mice were normal in size and in reproductive and social behavior, and their complete blood count showed no significant differences from wildtype. The mutation did not alter expression of integrin subunits and other related proteins. However, in vitro analysis showed that Cd11b I332G increased adhesion of neutrophils to fibrinogen, resulting in impaired chemotaxis. In vivo, Cd11b I332G reduced or delayed recruitment of inflammatory cells during acute inflammation and reduced cytokine secretion by macrophages. Activation of Cd11b protected the mice against development of atherosclerosis in the setting of hyperlipidemia via reduced macrophage recruitment into atherosclerotic lesions.
Arnaout, M. A., Gupta, S. K., Pierce, M. W., Tenen, D. G. Amino acid sequence of the alpha subunit of human leukocyte adhesion receptor Mo1 (complement receptor type 3). J. Cell Biol. 106: 2153-2158, 1988. [PubMed: 2454931] [Full Text: https://doi.org/10.1083/jcb.106.6.2153]
Arnaout, M. A., Remold-O'Donnell, E., Pierce, M. W., Harris, P., Tenen, D. G. Molecular cloning of the alpha-subunit of human and guinea pig leukocyte adhesion glycoprotein Mo1: chromosomal localization and homology to the alpha-subunits of integrins. Proc. Nat. Acad. Sci. 85: 2776-2780, 1988. [PubMed: 2833753] [Full Text: https://doi.org/10.1073/pnas.85.8.2776]
Callen, D. F., Chen, L. Z., Nancarrow, J., Whitmore, S. A., Apostolou, S., Thompson, A. D., Lane, S. A., Stallings, R. L., Hildebrand, C. E., Harris, P. G., Sutherland, G. R. Current state of the physical map of human chromosome 16. (Abstract) Cytogenet. Cell Genet. 58: 1998 only, 1991.
Cao, C., Lawrence, D. A., Li, Y., Von Arnim, C. A. F., Herz, J., Su, E. J., Makarova, A., Hyman, B. T., Strickland, D. K., Zhang, L. Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. EMBO J. 25: 1860-1870, 2006. [PubMed: 16601674] [Full Text: https://doi.org/10.1038/sj.emboj.7601082]
Chen, J., Zhong, M.-C., Guo, H., Davidson, D., Mishel, S., Lu, Y., Rhee, I., Perez-Quintero, L.-A., Zhang, S., Cruz-Munoz, M.-E., Wu, N., Vinh, D. C., Sinha, M., Calderon, V., Lowell, C. A., Danska, J. S., Veillette, A. SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin. Nature 544: 493-497, 2017. [PubMed: 28424516] [Full Text: https://doi.org/10.1038/nature22076]
Corbi, A. L., Kishimoto, T. K., Miller, L. J., Springer, T. A. The human leukocyte adhesion glycoprotein Mac-1 (complement receptor type 3, CD11b) alpha subunit: cloning, primary structure, and relation to the integrins, von Willebrand factor and factor B. J. Biol. Chem. 263: 12403-12411, 1988. [PubMed: 2457584]
Corbi, A. L., Larson, R. S., Kishimoto, T. K., Springer, T. A., Morton, C. C. Chromosomal location of the genes encoding the leukocyte adhesion receptors LFA-1, Mac-1 and p150,95: identification of a gene cluster involved in cell adhesion. J. Exp. Med. 167: 1597-1607, 1988. [PubMed: 3284962] [Full Text: https://doi.org/10.1084/jem.167.5.1597]
Martinez, L., Li, X., Ramos-Echazabal, G., Faridi, H., Zigmond, Z. M., Santos Falcon, N., Hernandez, D. R., Shehadeh, S. A., Velazquez, O. C., Gupta, V., Vazquez-Padron, R. I. A genetic model of constitutively active integrin CD11b/CD18. J. Immun. 205: 2545-2553, 2020. [PubMed: 32938725] [Full Text: https://doi.org/10.4049/jimmunol.1901402]
Pierce, M. W., Remold-O'Donnell, E., Todd, R. F., III, Arnaout, M. A. N-terminal sequence of human leukocyte glycoprotein Mo1: conservation across species and homology to platelet IIb/IIIa. Biochim. Biophys. Acta 874: 368-371, 1986. [PubMed: 3539202] [Full Text: https://doi.org/10.1016/0167-4838(86)90037-3]
Ranganathan, S., Cao, C., Catania, J., Migliorini, M., Zhang, L., Strickland, D. K. Molecular basis for the interaction of low density lipoprotein receptor-related protein 1 (LRP1) with integrin alpha-M/beta-2: identification of binding sites within alpha-M/beta-2 for LRP1. J. Biol. Chem. 286: 30535-30541, 2011. [PubMed: 21676865] [Full Text: https://doi.org/10.1074/jbc.M111.265413]
Simon, D. I., Chen, Z., Seifert, P., Edelman, E. R., Ballantyne, C. M., Rogers, C. Decreased neointimal formation in Mac-1 -/- mice reveals a role for inflammation in vascular repair after angioplasty. J. Clin. Invest. 105: 293-300, 2000. [PubMed: 10675355] [Full Text: https://doi.org/10.1172/JCI7811]
Springer, T. A., Teplow, D. B., Dreyer, W. J. Sequence homology of the LFA-1 and Mac-1 leukocyte adhesion glycoproteins and unexpected relation to leukocyte interferon. Nature 314: 540-542, 1985. [PubMed: 3887182] [Full Text: https://doi.org/10.1038/314540a0]