Integrin alpha M

ITGAM
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1BHO, 1BHQ, 1IDN, 1IDO, 1JLM, 1M1U, 1MF7, 1N9Z, 1NA5, 2LKE, 2LKJ, 3Q3G, 3QA3, 4M76, 4XW2
Identifiers
Aliases	ITGAM, CD11B, CR3A, MAC-1, MAC1A, MO1A, SLEB6, integrin subunit alpha M
External IDs	OMIM: 120980; MGI: 96607; HomoloGene: 526; GeneCards: ITGAM; OMA:ITGAM - orthologs
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p11.2 Start 31,259,967 bp[1] End 31,332,892 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 F3 Start 127,661,812 bp[2] End 127,717,663 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte trabecular bone bone marrow blood bone marrow cells spleen appendix upper lobe of left lung decidua Top expressed in granulocyte bone marrow ileum jejunum spleen dentate gyrus of hippocampal formation granule cell hippocampus proper esophagus striatum of neuraxis uterus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding protein binding protein heterodimerization activity heat shock protein binding amyloid-beta binding complement component C3b binding cargo receptor activity Cellular component extracellular exosome plasma membrane cell surface membrane integral component of membrane integrin complex extracellular space specific granule membrane tertiary granule membrane external side of plasma membrane integrin alphaM-beta2 complex plasma membrane raft membrane raft Biological process ectodermal cell differentiation toll-like receptor 4 signaling pathway integrin-mediated signaling pathway leukocyte migration extracellular matrix organization cell adhesion neutrophil degranulation microglial cell activation immune system process receptor-mediated endocytosis phagocytosis, engulfment cytokine-mediated signaling pathway positive regulation of superoxide anion generation positive regulation of neutrophil degranulation innate immune response negative regulation of dopamine metabolic process positive regulation of protein targeting to membrane amyloid-beta clearance cell-cell adhesion via plasma-membrane adhesion molecules complement-mediated synapse pruning vertebrate eye-specific patterning positive regulation of neuron death positive regulation of microglial cell activation positive regulation of microglial cell mediated cytotoxicity cell surface receptor signaling pathway involved in cell-cell signaling positive regulation of prostaglandin-E synthase activity forebrain development apoptotic signaling pathway positive regulation of hippocampal neuron apoptotic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3684 16409 Ensembl ENSG00000169896 ENSMUSG00000030786 UniProt P11215 P05555 RefSeq (mRNA) NM_000632 NM_001145808 NM_001082960 NM_008401 RefSeq (protein) NP_000623 NP_001139280 n/a Location (UCSC) Chr 16: 31.26 – 31.33 Mb Chr 7: 127.66 – 127.72 Mb PubMed search [3] [4]
Wikidata
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Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (α_Mβ₂) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3).^[5] ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B). The second chain of α_Mβ₂ is the common integrin β₂ subunit known as CD18, and integrin α_Mβ₂ thus belongs to the β₂ subfamily (or leukocyte) integrins.^[6]

α_Mβ₂ is expressed on the surface of many leukocytes involved in the innate immune system, including monocytes, granulocytes, macrophages, and natural killer cells ^[5] and subsets of T and B cells.^[7] It mediates inflammation by regulating leukocyte adhesion and migration and has been implicated in several immune processes such as phagocytosis, cell-mediated cytotoxicity, chemotaxis and cellular activation.^[5] It is involved in the complement system due to its capacity to bind inactivated complement component 3b (iC3b).^[8] The ITGAM (alpha) subunit of integrin α_Mβ₂ is directly involved in causing the adhesion and spreading of cells but cannot mediate cellular migration without the presence of the β2 (CD18) subunit.^[5]

In genomewide association studies, single nucleotide polymorphisms in ITGAM had the strongest association with systemic lupus erythematosus, with an odds ratio of 1.65 for the T allele of rs9888739 and lupus.^[9][10]

In histopathology, immunohistochemistry with antibodies against CD11B is frequently used to identify macrophages and microglia.

CD11b, as an integrin molecule on the surface of leukocytes, plays an important role in cell migration, adhesion, and transmigration across blood vessels, because it can bind to components of extracellular matrix and intracellular adhesion molecules (ICAMs) on the endothelial surface. This process is important for leukocyte recruitment into the site of inflammation.^[7]

Moreover, there are other important processes with CD11b involvement, more precisely Mac-1 integrin involvement as a whole. One of which is phagocytosis of opsonised particles by a complement component iC3b. Such opsonised particles could be bacteria, apoptotic cells, and even immune complexes. CD11b binding to iC3b leads to a production of anti-inflammatory cytokines, e.g., interleukin 10 (IL-10) and tumour growth factor beta (TGFβ). This process is important for regulation of the inflammatory milieu.^[7][11]

CD11b is also involved in the differentiation of osteoclasts, bone remodelling cells. Mac-1 is expressed in osteoclast progenitors, and it seems that it is a part of a negative feedback of osteoclastogenesis.^[11] CD11b also modulates other functions of leukocytes, e.g. oxidative burst, apoptosis, binding of fibrinogen etc.^[12]

On circulating leukocytes, CD11b is expressed in a closed conformation. The switch into an active conformation follows quickly after the stimulation of toll-like receptors (TLR) of the leukocytes.^[7] Once activated, CD11b can bind its ligands with high affinity, e.g., binding of ICAM-1 or ICAM-2 molecules on endothelium and subsequent adhesion. CD11b signalling is also known to interfere with TLR signalling in the cell. TLR stimulation results in the production of pro-inflammatory cytokines, e.g., IL-6 and IL-1β, via a series of phosphorylation of signalling factors, one of which is the NF-κB transcription factor.^[13] This signalling is in fact negatively affected by CD11b signalling. Consequently, this leads to a reduced activation of NF-κB and lower production of above-mentioned pro-inflammatory cytokines. To conclude, CD11b signalling negatively regulates leukocyte activation after TLR stimulation.^[7][12] Beside TLR signalling, CD11b also negatively regulates B cell receptor (BCR) signalling, and it suppresses T cell activation and dendritic cell maturation and function.^[7]

Regarding CD11b function, it is apparent that it plays an important role in immune cell regulation. Once this regulation is disrupted, it may lead to a higher susceptibility to inflammatory and autoimmune diseases. Some examples would be systemic lupus erythematosus (SLE), lupus nephritis and certain types of cancer.^[12][14]

Genome Wide Association Studies helped to uncover 3 main single nucleotide polymorphisms (SNPs) in CD11b, that are associated with the risk of developing SLE, cardiovascular disease, and lupus nephritis (a complication usually occurring along with SLE). These SNPs are: rs1143679 (R77H), rs1143678 (P1146S), and rs1143683 (A858V) and they result in the lower ability of CD11b to properly bind ICAM-1 and iC3b, thus decreased cell adhesion and phagocytosis. Reduced ability to negatively regulate the production of pro-inflammatory cytokines IL-6, IL-1β, and tumour necrosis factor α (TNFα) after TLR stimulation have been also observed in these mutations.^[12]

CD11b plays a protective role during SLE and lupus nephritis owing to its anti-inflammatory properties. Lupus nephritis is characterised by the accumulation of immune complexes in kidneys and overall immune infiltration into kidneys, which results in renal damage. This debilitating complication of SLE is associated with the above-mentioned mutations in CD11b. Patients with ITGAM SNPs have higher serum levels of interferon type I (IFN-I), which is one of the risk factors for developing SLE and lupus nephritis. Moreover, higher levels of other pro-inflammatory cytokines IL-6, IL-1β and TNFα after TLR stimulation, observed in patients with ITGAM SNPs, further drive the inflammation during this disease causing more tissue damage and creation of immune complexes.^[7][12]

Hence, CD11b represents a possible therapeutic target for the treatment of SLE. Indeed, many attempts to target CD11b have been made. Firstly, antibody-based therapy which proved to be ineffective in the case of CD11b.^[15] However, other therapies using small allosteric CD11b agonists seem to be a promising tool as their activation of CD11b leads to a regulation of TLR-dependant pro-inflammatory pathways and protection from renal damage.^[12]

CD11b seems to be a potent player in managing certain types of solid tumours. Even though nowadays many tools for cancer treatment exist, multiple factors of this illness remain a challenging topic. One of them are myeloid-derived suppressor cells (MDSC) and tumour-associated macrophages (TAMs), which are myeloid cells present in the tumour microenvironment possessing suppressor properties, thus favouring the tumour growth. TAMs, however, do not have only tumour-promoting properties, they can also display tumour-inhibiting properties. It depends on their stimulation. The tumour-inhibiting properties include the production of pro-inflammatory cytokines and the ability to present antigens.^[14]

Using CD11b agonists seems to be of importance in tumour treatment. Agonist that stabilize CD11b in its active conformation result in higher adhesion of CD11b to its endothelial ligands, consequently impair the ability of transendothelial migration to the site of inflammation. Such agonist therapy is under development and one promising candidate, GB1275, is currently in its first clinical phase at the beginning of 2023. This agonist of CD11b shows impaired transmigration of suppressive TAMs into the site of tumour and modulation of TAMs towards pro-inflammatory phenotype with higher antigen presentation and production of pro-inflammatory cytokines. Therefore, promising better tumour inhibition.^[14]

• integrin

• Integrin+alphaM at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Mouse CD Antigen Chart
• Human CD Antigen Chart
• ITGAM Info with links in the Cell Migration Gateway Archived 2014-12-11 at the Wayback Machine