ICAM-1, also known as CD54, is a cell surface glycoprotein. It acts as a biosensor, transducing outside-in signals through its cytoplasmic domain, which binds to the extracellular domain and then to the actin cytoskeleton. ICAM-1 has emerged as a key regulator of many important tissue functions, both at the onset and resolution of pathological conditions. ICAM-1 plays a crucial role in the development and progression of cardiovascular disease, autoimmune disorders, and tumors.

ICAM1 expression distribution

ICAM-1 is expressed in various cell types, including epithelial cells, keratinocytes, fibroblasts, and immune cells, such as macrophages and Langerhans cells, and plays a crucial role in cell-cell and cell-extracellular matrix interactions, cell signaling, and immune processes.

(Data source: uniprot)

Structure of ICAM1

ICAM-1 is located on chromosome 19p13 and is a cell surface glycoprotein of the CAM immunoglobulin (Ig) superfamily. It is a type I transmembrane protein composed of five extracellular Ig-like domains, a transmembrane domain, and a short cytoplasmic tail. The molecular weight of ICAM-1 varies between 60 and 114 kDa, depending on the degree of glycosylation of the immunoglobulin domains. These glycosylated immunoglobulin domains mediate the interaction between ICAM-1 and its ligands. ICAM-1's two ligands, LFA-1 and Mac-1, bind to its Ig domains 1 and 3, respectively. ICAM-1 dimerizes and aggregates through homotypic binding between immunoglobulin domains 3 and 4, significantly increasing the binding affinity of ICAM-1 for its ligands. ICAM-1 exists in two forms: membrane-bound and soluble ICAM-1 (sICAM-1).

(Data source: Guerra-Espinosa C, et al. Cells. 2024)

Function of ICAM1

ICAM-1 acts as an adhesion molecule and signaling receptor on many cell types to initiate inflammatory responses, initiate resolution and healing, and regulate tumor cell survival and dissemination.

The function of ICAM-1 in inflammation: It regulates leukocyte effector functions during inflammation (PMN release of ROS, dendritic cell priming and activation of T cells, and macrophage endocytosis and polarization). ICAM-1 contributes to tissue repair by promoting neovascularization and re-epithelialization. sICAM-1 has been shown to promote both pro- and anti-inflammatory responses. Low levels of sICAM-1 have been shown to trigger activation of NFκB and ERK, leading to the release of inflammatory cytokines such as macrophage inflammatory protein ( MIP ) -1a, MIP-2, TNFα, IFNγ, and IL-6. Conversely, high levels of sICAM-1 enhance EC migration and angiogenesis, competitively inhibit leukocyte-EC interactions, and promote the repair activity of immune cells .

Function of ICAM-1 in the tumor microenvironment: It promotes carcinogenesis by promoting the extravasation and survival of circulating tumor cells. Through β2-integrin expressed by immune cells, ICAM-1 can promote CTC-leukocyte aggregation. The association of CTC clusters with polymorphonuclear neutrophils increases tumor cell survival and proliferation. ICAM-1 expressed by endothelial cells can promote the capture and extravasation of tumors expressing β2-integrin.

(Data source: Bui TM, Wiesolek HL, Sumagin R. J Leukoc Biol. 2020)

ICAM1 and disease

ICAM-1 plays an important role in various cardiovascular diseases, such as atherosclerosis, myocardial infarction, coronary artery disease, and thrombosis. In acute myocardial infarction (AMI), ICAM-1 influences the inflammatory response by promoting leukocyte infiltration, endothelial cell proliferation, and neutrophil recruitment, which is a key stage in the inflammatory process of AMI.

(Data source: Singh V, et al. Clin Chim Acta. 2023)

ICAM-1 is overexpressed in triple-negative breast cancer (TNBC) and is associated with tumor invasion and metastasis . Atorvastatin effectively inhibits ICAM-1 expression in tumor cells, reduces neutrophil infiltration, and downregulates the MAPK signaling pathway. This suggests that atorvastatin, as a potential treatment for TNBC, may reduce the malignant characteristics of TNBC by targeting the CD11b-ICAM-1 interaction.

(Data source: Yang C, et al. Cell Commun Signal. 2024)