A small molecule that inhibits the interaction of paxillin and alpha 4 integrin inhibits accumulation of mononuclear leukocytes at a site of inflammation

• Published in: The Journal of biological chemistry 2010-03, Vol.285 (13), p.9462-9469
• Main Authors: Kummer, Christiane, Petrich, Brian G, Rose, David M, Ginsberg, Mark H
• Format: Article
• Language: English
• Subjects: Animals; Cell Movement; CHO Cells; Cricetinae; Cricetulus; Humans; Inflammation; Integrin alpha4 - metabolism; Jurkat Cells; Leukocytes, Mononuclear - metabolism; Male; Mice; Mice, Inbred C57BL; Models, Biological; Paxillin - metabolism; Signal Transduction
• ISSN: 1083-351X
• DOI: 10.1074/jbc.M109.066993

Extracellular antagonists of alpha 4 integrin are an effective therapy for several autoimmune and inflammatory diseases; however, these agents that directly block ligand binding may exhibit mechanism-based toxicities. Inhibition of alpha 4 integrin signaling by mutations of alpha 4 that block paxillin binding inhibits inflammation while limiting mechanism-based toxicities. Here, we test a pharmacological approach by identifying small molecules that inhibit the alpha 4 integrin-paxillin interaction. By screening a large (approximately 40,000-compound) chemical library, we identified a noncytotoxic inhibitor of this interaction that impaired integrin alpha 4-mediated but not alpha L beta 2-mediated Jurkat T cell migration. The identified compound had no effect on alpha 4-mediated migration in cells bearing the alpha 4(Y991A) mutation that disrupts the alpha 4-paxillin interaction, establishing the specificity of its action. Administration of this compound to mice led to impaired recruitment of mononuclear leukocytes to a site of inflammation in vivo, whereas an isomer that does not inhibit the alpha 4-paxillin interaction had no effect on alpha 4-mediated cell migration, cell spreading, or recruitment of leukocytes to an inflammatory site. Thus, a small molecule inhibitor that interferes with alpha 4 integrin signaling reduces alpha 4-mediated T cell migration in vivo, thus providing proof of principle for inhibition of alpha 4 integrin signaling as a target for the pharmacological reduction of inflammation.