Integrin alpha M (ITGAM) is one protein subunit that forms heterodimericintegrin alpha-M beta-2 (αMβ2) 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 αMβ2 is the common integrin β2 subunit known as CD18, and integrin αMβ2 thus belongs to the β2 subfamily (or leukocyte) integrins.[6]
αMβ2 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 αMβ2 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]
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]
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]
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]
↑Crow MK (February 2008). "Collaboration, genetic associations, and lupus erythematosus". The New England Journal of Medicine. 358 (9): 956–961. doi:10.1056/NEJMe0800096. PMID18204099.
Todd RF, Petty HR (May 1997). "Beta 2 (CD11/CD18) integrins can serve as signaling partners for other leukocyte receptors". The Journal of Laboratory and Clinical Medicine. 129 (5): 492–498. doi:10.1016/S0022-2143(97)90003-2. PMID9142045.
Schymeinsky J, Mócsai A, Walzog B (August 2007). "Neutrophil activation via beta2 integrins (CD11/CD18): molecular mechanisms and clinical implications". Thrombosis and Haemostasis. 98 (2): 262–273. doi:10.1160/th07-02-0156. PMID17721605. S2CID41094726.
