ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis

Abstract

ICAM-1 is a cell surface glycoprotein and an adhesion receptor that is best known for regulating leukocyte recruitment from circulation to sites of inflammation. However, in addition to vascular endothelial cells, ICAM-1 expression is also robustly induced on epithelial and immune cells in response to inflammatory stimulation. Importantly, ICAM-1 serves as a biosensor to transduce outside-in-signaling via association of its cytoplasmic domain with the actin cytoskeleton following ligand engagement of the extracellular domain. Thus, ICAM-1 has emerged as a master regulator of many essential cellular functions both at the onset and at the resolution of pathologic conditions. Because the role of ICAM-1 in driving inflammatory responses is well recognized, this review will mainly focus on newly emerging roles of ICAM-1 in epithelial injury-resolution responses, as well as immune cell effector function in inflammation and tumorigenesis. ICAM-1 has been of clinical and therapeutic interest for some time now; however, several attempts at inhibiting its function to improve injury resolution have failed. Perhaps, better understanding of its beneficial roles in resolution of inflammation or its emerging function in tumorigenesis will spark new interest in revisiting the clinical value of ICAM-1 as a potential therapeutic target.

Keywords: Inflammation; adhesion molecules; immune cells; metastasis; migration; tumorigenesis; wound healing.

FIGURE 1. ICAM-1 expression on endothelial, epithelial, and immune cells.

Representative immunofluorescence images show ICAM-1 expression on the surface of intestinal epithelial cells, Caco2 (left, co-stained with the junctional molecule ZO-1), and on macrophages and endothelial cells in inflamed mouse colon tissue (right). Colon inflammation was induced by dextran sodium sulfate (DSS) treatment (3% weight/volume). Following 4 d of treatment colon tissue was extracted, sectioned, and stained using standard protocols. ICAM-1 expressing, F4/80 positive tissue MΦs shown by white arrows, (v) depicts blood vessels, the white dashed line separates the muscularis and mucosa layers. Scale bars represent 20μm

FIGURE 2. Potential mechanisms of action by which ICAM-1 may promote tumor metastasis.

(1) Via binding to β₂-integrins expressing tumor cells, ICAM-1 may support homotypic clustering of circulating tumor cells (CTCs). CTC clusters showed increased survival and metastatic potential. (2) Via β₂-integrins expressed by immune cells, ICAM-1 can promote CTC-leukocyte clustering β₂-integrin. Association of CTC clusters with polymorphonuclear neutrophils increased survival and proliferation of tumor cells. (3) ICAM-1 expressed by endothelial cells can facilitate capture and extravasation of β_2-integrin-expressing tumor hijacking transendothelial migration mechanisms used by migrating leukocytes

FIGURE 3. ICAM-1 function in tissue homeostasis and disease.

Schematic representation of key physiologic processes regulated by ICAM-1. These include leukocyte-endothelial cell interactions and TEM, regulation of leukocyte effector function in inflammation (ROS release by PMNs, T-cell priming and activation by dendritic cells, macrophage efferocytosis and polarization), tissue repair by promoting neovascularization and reepithelialization, and carcinogenesis by facilitating circulating tumor cell extravasation and survival