The role of ICAM-1 isoforms in neutrophil recruitment to liver

Abstract

Abstract Intercellular adhesion molecule-1 (ICAM-1) is one of important molecules involved in neutrophil recruitment and works as a ligand for integrin leukocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) on neutrophils. Full-length ICAM-1 consists of five domains (D1–D2–D3–D4–D5) and D1 is a ligand binding domain for LFA-1 and D3 is for Mac-1. In addition, several alternative splicing variants exist as shown in transgenic mice. ICAM-1 Exon 4 deletion mice express D1D4D5, D1D2D5 and D1D5, while exon 5 deletion mice express D1D2D3D5, D1D2D5 and D1D5. The previous report of sepsis model showed exon 4 deletion mice showed significant reduction in neutrophil recruitment to liver with no mortality, while almost all of exon 5 deletion mice died with a large neutrophil recruitment. The mortality of WT mice was better than that of exon 5 deletion mice and worse than that of exon 4 deletion mice. These results suggest that ICAM-1 isoforms have functional roles in neutrophil recruitment. Our sepsis model demonstrated that neutrophil recruitment to liver was not affected in LFA-1 knockout mice and was reduced significantly in Mac-1 knockout mice. We speculated that ICAM-1 isoforms have functional roles via the interaction with Mac-1. Our PCR experiments demonstrated that liver highly expressed full length ICAM-1, D1D3D4D5 and D1D2D3D5 with full length ICAM-1 at the most abundant amount. Both D1D3D4D5 and D1D2D3D5 contain D3 and potentially bind to Mac-1. We expressed D1D3D4D5 and D1D2D3D5 along with full-length ICAM-1 in 293T cells, and examined the binding to Mac-1. Our preliminary data suggest that D1D2D3D5 bound more strongly to Mac-1 than full-length, supporting our hypothesis.