Molecules that target key events in macrophage migration during inflammation

Abstract

Leukocyte migration is an essential mechanism in host immunity. However, once leukocytes have been recruited to the site of tissue injury, their activity constitutes a leading cause of inflammation and tissue or vessel wall injury. The process of migration is tightly regulated and mediated by the temporal and spatial presentation of molecules expressed on the migrating leukocytes, the endothelium and on other cells at the site of recruitment. In recent years, novel compounds have been developed to impede crucial aspects of cellular migration, such as adhesion to the vessel wall transendothelial migration and movement along chemotactic gradients to the site of injury. These novel compounds specifically target monocyte recruitment and represent a more defined course to control chronic inflammation than the use of existing broad spectrum anti-inflammatories. Key areas of progress have involved directly targeting the molecules that mediate the migration process, such as adhesion molecules and chemokines. In an attempt to inhibit or block the expression and binding of adhesion molecules, molecular species under development include monoclonal antibodies, peptide fragments and antisense oligonucleotides. In addition, negating the pro-inflammatory actions of chemokines can reduce chronic deleterious immune responses. As a result, several novel approaches have been developed and patented. Three classes of molecular antagonists have been targeted: small molecule inhibitors of chemokine receptors, modified chemokines or N-terminal peptides and neutralising monoclonal antibodies raised to bind to, and thus neutralise, chemokines or their receptors. This review will focus on these novel approaches, the progress which has been made and likely successful outcomes.

• adhesion molecules
• anti-inflammation
• chemokines
• macrophage