Integrin alpha M (ITGAM) is one protein subunit that formsheterodimericintegrin alpha-M beta-2 (αMβ2) molecule, also known asmacrophage-1 antigen (Mac-1) orcomplement receptor 3 (CR3).[5] ITGAM is also known as CR3A, andcluster of differentiation molecule 11B (CD11B). The second chain of αMβ2 is the common integrin β2 subunit known asCD18, and integrin αMβ2 thus belongs to the β2 subfamily (or leukocyte) integrins.[6]
αMβ2 is expressed on the surface of manyleukocytes involved in theinnate immune system, includingmonocytes,granulocytes,macrophages, andnatural killer cells[5] and subsets of T and B cells.[7] It mediates inflammation by regulating leukocyteadhesion and migration and has been implicated in several immune processes such asphagocytosis, cell-mediated cytotoxicity,chemotaxis and cellular activation.[5] It is involved in thecomplement system due to its capacity to bind inactivatedcomplement 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 withsystemic lupus erythematosus, with an odds ratio of 1.65 for the T allele of rs9888739 and lupus.[9][10]
Inhistopathology, immunohistochemistry with antibodies against CD11B is frequently used to identifymacrophages andmicroglia.
CD11b, as anintegrin molecule on the surface ofleukocytes, plays an important role in cell migration, adhesion, andtransmigration acrossblood vessels, because it can bind to components ofextracellular matrix and intracellular adhesion molecules (ICAMs) on theendothelial surface. This process is important for leukocyte recruitment into the site ofinflammation.[7]
Moreover, there are other important processes with CD11b involvement, more precisely Mac-1 integrin involvement as a whole. One of which isphagocytosis of opsonised particles by acomplement component iC3b. Such opsonised particles could bebacteria,apoptotic cells, and evenimmune complexes. CD11b binding to iC3b leads to a production of anti-inflammatorycytokines, e.g.,interleukin 10 (IL-10) andtumour growth factor beta (TGFβ). This process is important for regulation of the inflammatory milieu.[7][11]
CD11b is also involved in the differentiation ofosteoclasts, 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 offibrinogen etc.[12]
On circulatingleukocytes, CD11b is expressed in a closed conformation. The switch into an active conformation follows quickly after the stimulation oftoll-like receptors (TLR) of theleukocytes.[7] Once activated, CD11b can bind its ligands with high affinity, e.g., binding ofICAM-1 orICAM-2 molecules onendothelium and subsequent adhesion. CD11b signalling is also known to interfere withTLR signalling in the cell.TLR stimulation results in the production ofpro-inflammatory cytokines, e.g.,IL-6 andIL-1β, via a series ofphosphorylation of signalling factors, one of which is theNF-κB transcription factor.[13] This signalling is in fact negatively affected by CD11b signalling. Consequently, this leads to a reduced activation ofNF-κB and lower production of above-mentionedpro-inflammatory cytokines. To conclude, CD11b signalling negatively regulatesleukocyte activation afterTLR stimulation.[7][12] BesideTLR signalling, CD11b also negatively regulatesB cell receptor (BCR) signalling, and it suppressesT cell activation anddendritic 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 andautoimmune diseases. Some examples would besystemic lupus erythematosus (SLE),lupus nephritis and certain types ofcancer.[12][14]
Genome Wide Association Studies helped to uncover 3 mainsingle nucleotide polymorphisms (SNPs) in CD11b, that are associated with the risk of developingSLE,cardiovascular disease, andlupus nephritis (a complication usually occurring along withSLE). TheseSNPs are: rs1143679 (R77H), rs1143678 (P1146S), and rs1143683 (A858V) and they result in the lower ability of CD11b to properly bindICAM-1 andiC3b, thus decreased cell adhesion andphagocytosis. Reduced ability to negatively regulate the production ofpro-inflammatory cytokinesIL-6,IL-1β, andtumour necrosis factor α (TNFα) afterTLR stimulation have been also observed in thesemutations.[12]
CD11b plays a protective role duringSLE andlupus nephritis owing to itsanti-inflammatory properties.Lupus nephritis is characterised by the accumulation ofimmune complexes in kidneys and overall immune infiltration into kidneys, which results in renal damage. This debilitating complication ofSLE is associated with the above-mentioned mutations in CD11b. Patients withITGAMSNPs have higher serum levels ofinterferon type I (IFN-I), which is one of the risk factors for developingSLE andlupus nephritis. Moreover, higher levels of otherpro-inflammatory cytokinesIL-6,IL-1β andTNFα afterTLR stimulation, observed in patients withITGAMSNPs, further drive theinflammation during this disease causing more tissue damage and creation ofimmune complexes.[7][12]
Hence, CD11b represents a possible therapeutic target for the treatment ofSLE. 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 CD11bagonists seem to be a promising tool as their activation of CD11b leads to a regulation ofTLR-dependant pro-inflammatory pathways and protection from renal damage.[12]
CD11b seems to be a potent player in managing certain types ofsolid tumours. Even though nowadays many tools forcancer treatment exist, multiple factors of this illness remain a challenging topic. One of them aremyeloid-derived suppressor cells (MDSC) andtumour-associated macrophages (TAMs), which aremyeloid cells present in thetumour microenvironment possessing suppressor properties, thus favouring thetumour 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 ofpro-inflammatory cytokines and the ability topresent antigens.[14]
Using CD11b agonists seems to be of importance intumour treatment. Agonist that stabilize CD11b in its active conformation result in higher adhesion of CD11b to its endothelial ligands, consequently impair the ability oftransendothelial migration to the site ofinflammation. Suchagonist 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 impairedtransmigration of suppressiveTAMs into the site oftumour and modulation ofTAMs towards pro-inflammatory phenotype with higherantigen presentation and production ofpro-inflammatory cytokines. Therefore, promising better tumour inhibition.[14]
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