Cell-to-cell adhesion as well as the interaction of cells with the extracellular matrix are key phenomena in different physiological and pathological conditions, including embryogenesis, blood coagulation, lymphocyte homing, immune response, angiogenesis, metastasis, thrombosis and inflammation1, 2. Thus, it has been widely proposed that cell adhesion molecules are an important therapeutic target in a wide array of diseases with high impact on public health, including atherosclerosis, thromboembolic disorders, cancer, graft rejection and autoimmune inflammatory conditions1, 2. However, anti-adhesion therapy with either biological agents (mainly blocking monoclonal antibodies, mAb's) or chemical inhibitors (mainly synthetic peptides) has not yet fulfilled these expectations and has not been devoid of undesirable effects3, 4. In this context, the research team of Gupta at the University of Miami, recently published an interesting article employing an alternative approach for the pharmacological inhibition of leukocyte extravasation, thus blocking the inflammatory phenomenon5. According to this report, novel pharmacological agents (“leukadherins”) effectively inhibit the inflammatory phenomenon, with no apparent toxicity, which may constitute a major step ahead in this area.

In the work of the research team of Gupta5, three synthetic compounds called leukadherins-1 to -3 were identified by their ability to increase the adhesion of K562 cells expressing Mac-1 to fibrinogen, a ligand of this integrin. By using different experimental approaches and by in silico analysis, these authors concluded that leukadherins bind to the A domain of Mac-1, inducing a high-affinity conformation of this integrin. Accordingly, leukadherins increased the adhesion of leukocytes mediated by Mac-1 but inhibited their migration and extravasation in vivo. Furthermore, leukadherins exerted a significant therapeutic effect in three different models of inflammatory disease (peritonitis, vascular neointimal thickening and glomerulonephritis), with no apparent toxicity on leukocytes or endothelium, nor evidence of side-effects. Interestingly, additional experiments showed that leukadherins were more effective than a blocking anti-Mac-1 mAb. Finally, by using a transgenic zebrafish model of neutrophil recruitment, these authors demonstrated that the effect of leukadherins was transient and reversed by their removal. It was concluded that leukadherins act as Mac-1 agonists, increasing the adhesion of leukocytes but blocking their transendothelial migration and inhibiting thus the inflammatory phenomenon.

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