Integrins are heterodimeric transmembrane proteins composed of α and β subunits that bind to the typical extracellular matrix and often serve as receptors for activating signaling events. Extracellular matrix proteins produced by fibroblasts (laminin, fibronectin, etc.) serve as ligands for integrins. CD11 and CD18, collectively referred to as "leukocyte" integrin proteins, mediate leukocyte adhesion during inflammatory responses to infection and wound repair.
(Data source: Marsico G, et al. Trends Cancer. 2018)
CD11 composition:
There are four CD11 subfamily members (CD11a, CD11b, CD11c, and CD11d): CD11a is a pan-leukocyte marker expressed by B and T lymphocytes, monocytes, macrophages, neutrophils, basophils, and eosinophils; CD11b is expressed by most granulocytes, monocytes/macrophages, NK cells, and B and T cell subsets; and CD11c is highly expressed on monocytes/macrophages, NK cells, and hairy cells. All four α integrins pair with the β2 chain of CD18.
(Data source Schittenhelm L, et al. Front Immunol. 2017)
CD11 structure:
The two chains of integrins are non-covalently dimerized. Each chain consists of several extracellular domains, a single transmembrane domain, and a short cytoplasmic tail. Their conformation and clustering largely regulate their ligand affinity and function at the cell membrane. Multiple factors influence integrin conformation and clustering, including inside-out signaling, outside-in signaling, and thermodynamic equilibrium. Four conserved conformations can be observed in CD11a-c, labeled: bent-closed, bent-open, extended-closed, and extended-open. The bent-closed conformation has low ligand affinity and is considered inactive. Stimulatory signals can activate integrins, causing the extracellular domain to expand into the extended-closed conformation before transitioning to the fully activated extended conformation. The bent-open conformation may allow for an alternative transition to the extended conformation by cis-ligands.
(Data source Blythe EN, et al. Front Immunol. 2021)
CD11 signaling pathway and regulation:
CD11/CD18 integrins are expressed on the surfaces of various immune cells, including T cells, B cells, dendritic cells, and granulocytes. They mediate the immune functions of these cells, primarily in three key areas: immune cell recruitment and migration, immune cell interactions, and immune cell signaling. For example, they participate in the migration, adhesion, and effector functions of granulocytes; mediate macrophage phagocytosis and signal transduction; regulate the maturation, migration, and antigen presentation (APC) function of dendritic cells; mediate T cell migration, activation, and differentiation; and participate in B cell homing, immune synapse formation, and the development of tolerance.
(Data source Schittenhelm L, et al. Front Immunol. 2017)
Clinical value of CD11:
CD11/CD18 mediates and regulates cell migration, adhesion, and effector functions. Abnormal or dysregulated CD11/CD18 integrin function is closely associated with diseases such as cancer, autoimmune diseases, inflammation, primary immunodeficiency, infection, and cardiovascular disease. Efalizumab, a fully human monoclonal antibody targeting CD11a, was previously approved for the treatment of psoriasis but was withdrawn due to the risk of progressive multifocal leukoencephalopathy. Another clinical trial drug, Rovelizumab, was discontinued due to clinical data failing to meet expected standards. Currently, no other drug is under development.
