Discovery of a startling star: chemotaxis and chemotactic inhibition by starfish MIFs.

I mmune cell recruitment is a crucial process in cell homing and vertebrate immunity, initiating powerful host innate and adaptive defense mechanisms. However, immune cell recruitment also critically contributes to the pathologic sequelae of events driving various inflammatory diseases in humans such as atherosclerosis. The recruitment process is executed by chemokines, which promote the directed migration and arrest of a variety of immune and inflammatory cells in a receptor-specific manner. Specificity and diversity is guaranteed by an impressive repertoire of chemokine ligands interacting with their G protein-coupled receptors (GPCRs). Several organisms including invertebrates do not express classical CC-, CXC-, C-, or CXXXC-chemokines or their proto-typical GPCR receptors, 1 suggesting that in those organisms, yet additional mechanisms controlling chemotactic immune cell migration are in place. In this issue of Immunology and Cell Biology, Furukawa et al. 2 identify two orthologs of macrophage migration inhibitory factor (MIF; i.e., ApMIF1 and ApMIF2) in the starfish Patiria (Asterina) pectinifera (Ap). Using starfish larvae in vivo, the authors demonstrate that the ApMIFs control the chemotactic recruitment of mesenchyme cells, that is, innate immune-like cells in starfish, in response to foreign substance challenge (Figure 1). The authors show that the ApMIFs phylogenetically cluster with human MIF and its homolog D-dopachrome tautomerase 3 (D-DT or MIF-2). 2 MIF is an evolutionarily conserved inflammatory cytokine 4 , and is a prototypical 'chemokine-like function' or 'atypical chemokine'. 5 MIF and other atypical chemokines are structurally distinct from classical chemokines, yet interact with classical chemokine receptors in a surprisingly specific manner. 6 Therefore , chemokine-like function chemokines enhance the complexity and redundancy in chemokine-driven host immune responses to assure rapid, fined-tuned migration and inflammatory responses of numerous cell types. 7 An elucidation of the responsible residues that underlie binding between atypi-cal chemokines and classical chemokine GPCRs is under intensive investigation. 6 Intriguingly, the functional knockdown experiments in starfish larvae performed by Furukawa et al. indicate that ApMIF1 and ApMIF2 behave antagonistically. Knockdown of ApMIF1 led to a strong elevation in mesenchyme cell recruitment, whereas interference with ApMIF2 ablated mesenchyme cell movement, suggesting that ApMIF2 has chemokine-like properties, whereas ApMIF1 serves as an inhibitor of cell migration. This opposing behavior is in contrast to what has been observed so far for the human MIF homologs. Although chemotaxis has not directly been studied, signaling studies in several cell models imply that the mammalian MIFs function in an accordant manner, amplifying each other. …