Differential ICAM-1 isoform expression regulates the development and progression of experimental autoimmune encephalomyelitis

Intercellular adhesion molecule-1 (ICAM-1) functions in leukocyte trafficking, activation, and the formation of the immunological synapse. ICAM-1 is a member of the immunoglobulin superfamily of adhesion proteins, which share a similar structure of repeating Ig-like domains. Many genes in this family, including ICAM-1, show alternative splicing leading to the production of different protein isoforms, although little functional information is available regarding the expression patterns, ligand interactions, and functions of these isoforms, especially those arising from the ICAM-1 gene. In this study, we show using different lines of mutant mice (Icam1tm1Jcgr and Icam1tm1Bay) that alterations in the expression of the alternatively spliced ICAM-1 isoforms can significantly influence the disease course during the development of EAE. Icam1tm1Jcgr mutant mice, unlike Icam1tm1Bay mutants, do not express isoforms containing the Mac-1 binding domain and had significantly attenuated of EAE. In contrast, Icam1tm1Bay mice developed severe EAE in both active and adoptive transfer models compared to both Icam1tm1Jcgr and wild type mice. We also observed that T cells from Icam1tm1Bay mice displayed increased proliferation kinetics and produced higher levels of IFN-γ compared to Icam1tm1Jcgr and wild type mice. Thus, our investigations show that the alternatively spliced ICAM-1 isoforms are functional, and play key roles during the progression of CNS inflammation and demyelination in EAE. Furthermore, our findings suggest that these isoforms may also play key roles in controlling the development of inflammatory diseases such as multiple sclerosis, possibly through differential engagement with ICAM-1 ligands such as Mac-1.