ICAM-2 regulates diapedesis hotspots by allowing neutrophil crawling against the direction of flow.

Abstract

Intercellular adhesion molecules (ICAMs) are cell surface proteins that play a crucial role in the body's immune response and inflammatory processes. ICAM-1 and ICAM-2 are two ICAM family members expressed on the surface of various cell types, including endothelial cells. They mediate the interaction between immune cells and endothelial cells, which are critical for the trafficking of leukocytes across the blood vessel wall during inflammation. Although it is clear that ICAM-1 plays a prominent role in the leukocyte extravasation cascade, it is less clear if ICAM-2 strengthens ICAM-1 function or has a separate function in the cascade. With CRISPR-Cas9 technology, endothelial cells were depleted for ICAM-1, -2, or both, and we found that neutrophils favored ICAM-1 over ICAM-2 to adhere to. However, the absence of only ICAM-2 resulted in neutrophils that were unable to find the transmigration hotspot, i.e., the preferred exit site. Moreover, we found that ICAM-2 deficiency prevented neutrophils to migrate against the flow. Due to this deficiency, we concluded that ICAM-2 helps neutrophils find the preferred exit sites and thereby contributes to efficient leukocyte extravasation.