ICAM-1 is a member of theimmunoglobulin superfamily, the superfamily of proteins includingantibodies andT-cell receptors. ICAM-1 is a transmembrane protein possessing anamino-terminus extracellular domain, a single transmembrane domain, and acarboxy-terminus cytoplasmic domain. The structure of ICAM-1 is characterized by heavyglycosylation, and the protein’s extracellular domain is composed of multiple loops created bydisulfide bridges within the protein. The dominant secondary structure of the protein is thebeta sheet, leading researchers to hypothesize the presence of dimerization domains within ICAM-1.[8]
The protein encoded by this gene is a type ofintercellular adhesion molecule continuously present in low concentrations in the membranes ofleukocytes andendothelial cells. Upon cytokine stimulation, the concentrations greatly increase. ICAM-1 can be induced byinterleukin-1 (IL-1) andtumor necrosis factor (TNF) and is expressed by the vascular endothelium,macrophages, andlymphocytes. ICAM-1 is a ligand forLFA-1 (integrin), a receptor found on leukocytes.[9] When activated, leukocytes bind to endothelial cells via ICAM-1/LFA-1 and then transmigrate into tissues.[10] LFA-1 has also been found in a soluble form,[11] which seems to bind and block ICAM-1.[12]
ICAM-1 is anendothelial- andleukocyte-associated transmembrane protein long known for its importance in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. More recently, ICAM-1 has been characterized as a site for the cellular entry of humanrhinovirus.[13] Because of these associations with immune responses, it has been hypothesized that ICAM-1 could function in signal transduction. ICAM-1 ligation produces proinflammatory effects such as inflammatory leukocyte recruitment by signaling through cascades involving a number of kinases, including the kinasep56lyn.
The presence of heavy glycosylation and other structural characteristics of ICAM-1 lend the protein binding sites for numerous ligands. ICAM-1 possesses binding sites for a number of immune-associated ligands. Notably, ICAM-1 binds to macrophage adhesion ligand-1 (Mac-1;ITGB2 /ITGAM),leukocytefunction associated antigen-1 (LFA-1), andfibrinogen. These three proteins are generally expressed on endothelial cells and leukocytes, and they bind to ICAM-1 to facilitate transmigration of leukocytes across vascular endothelia in processes such as extravasation and the inflammatory response. As a result of these binding characteristics, ICAM-1 has classically been assigned the function of intercellularadhesion.
Researchers began to question the role of ICAM-1 as a simple adhesion molecule upon discovering that ICAM-1 serves as the binding site for entry of the major group of human rhinovirus (HRV) into various cell types.[8] ICAM-1 also became known for its affinity forPlasmodium falciparum-infected erythrocytes (PFIE), acting synergistically in mediating adherence of PFIE to endothelium co-expressingCD36, providing more of a role for ICAM-1 in infectious disease.[15]
With the roles of ICAM-1 in cell-cell adhesion, extravasation, and infection more fully understood, a potential role for ICAM-1 in signal transduction was hypothesized. Most of the work involving ICAM-1 in recent years has focused on this central question as well as related questions. Researchers reasoned that, should ICAM-1 signal transduction prove to occur, it would be necessary to identify the mechanism of that signaling, the conditions and environment in which the signaling would occur, and the biological endpoints of any signaling cascades involved. Beyond its classically described functions as an adhesion and viral entry molecule, ICAM-1 has now been characterized convincingly as possessing a role in signal transduction. Furthermore, the signal-transducing functions of ICAM-1 seem to be associated primarily with proinflammatory pathways. In particular, ICAM-1 signaling seems to produce a recruitment of inflammatory immune cells such as macrophages and granulocytes.[16]
ICAM-1 may also participate in apositive feedback loop and compete withICAM-2 to maintain a proinflammatory environment conducive to leukocyte endothelial transmigration. At both the mRNA and protein levels of expression, ICAM-1 ligation was found to upregulate ICAM-1’s own expression in a positive-feedback loop. In addition, the expression ofRANTES mRNA and protein was also found to be upregulated by ICAM-1 ligation. RANTES, or Regulated upon Activation Normal T-cell Expressed and Secreted, is a cytokine that is an inflammatory mediator chemotactic for a variety of inflammatory immune cells such as granulocytes and macrophages.[17] However, much work remains to be done in fully characterizing the signaling of ICAM-1. The relationship between ICAM-1 and ICAM-2 signaling environments has not been established beyond mere correlation; a study linking ICAM signaling to actual modulation of an inflammatory environment in vivo has yet to be conducted. The reticular nature of signaling cascades necessitates that the downstream effectors of ICAM-1 mediated signaling through various kinases includingp56lyn,Raf-1, and theMAPKs are largely unknown. A more thorough study of the cross-talk between these signaling molecules may shed further light onto the biological endpoints produced by ICAM-1 ligation and signal transduction.
ICAM-1 has been implicated insubarachnoid hemorrhage (SAH). Levels of ICAM-1 are shown to be significantly elevated in patients with SAH over control subjects in many studies.[18][19] While ICAM-1 has not been shown to be directly correlated with cerebralvasospasm, a secondary symptom that affects 70% of SAH patients, treatment with anti-ICAM-1 reduced the severity of vasospasm.
ICAM-1 has an important role in ocular allergies recruiting pro-inflammatory lymphocytes and mast cells promoting atype I hypersensitivity reaction.
ICAM-1 is the primary entry receptor forCoxsackievirus A21, an oncolytic virus (brand name Cavatak, being developed byViralytics).[20]
CannabinoidCB2receptoragonists have been found to decrease the induction of ICAM-1 andVCAM-1 surface expression in human brain tissues and primary human brainendothelial cells (BMVEC) exposed to various pro-inflammatory mediators.[21]
^Katz FE, Parkar M, Stanley K, Murray LJ, Clark EA, Greaves MF (Jan 1985). "Chromosome mapping of cell membrane antigens expressed on activated B cells".European Journal of Immunology.15 (1):103–06.doi:10.1002/eji.1830150121.PMID3871395.S2CID6571761.
^Rothlein R, Dustin ML, Marlin SD, Springer TA (August 1986). "A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1".Journal of Immunology.137 (4):1270–4.doi:10.4049/jimmunol.137.4.1270.PMID3525675.S2CID70723.
^Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF, Lee KS (Oct 1998). "Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage".Journal of Neurosurgery.89 (4):559–67.doi:10.3171/jns.1998.89.4.0559.PMID9761049.
^Yusuf-Makagiansar H, Makagiansar IT, Hu Y, Siahaan TJ (Dec 2001). "Synergistic inhibitory activity of alpha- and beta-LFA-1 peptides on LFA-1/ICAM-1 interaction".Peptides.22 (12):1955–62.doi:10.1016/S0196-9781(01)00546-0.PMID11786177.S2CID54343441.
Chakravorty SJ, Craig A (Jan 2005). "The role of ICAM-1 in Plasmodium falciparum cytoadherence".European Journal of Cell Biology.84 (1):15–27.doi:10.1016/j.ejcb.2004.09.002.PMID15724813.
Lebedeva T, Dustin ML, Sykulev Y (Jun 2005). "ICAM-1 co-stimulates target cells to facilitate antigen presentation".Current Opinion in Immunology.17 (3):251–58.doi:10.1016/j.coi.2005.04.008.PMID15886114.
