The study, “Small Molecule–Mediated Activation of the Integrin CD11b/CD18 Reduces Inflammatory Disease,” was published September 6 in Science Signaling.
The multidisciplinary research team, headed by the Miller School’s Vineet Gupta, Ph.D., assistant professor of medicine, biochemistry and molecular biology and the founding co-director of the Peggy and Harold Katz Family Drug Discovery Center, discovered that activating the integrin CD11b/CD18—rather than blocking it as attempted in previous research—led to reduced tissue inflammation. The activation was spurred by leukadherins, novel small molecule compounds that were identified by the Gupta Laboratory at UM and were developed to specifically enhance the function of integrins, which are located on the surface of white blood cells, or leukocytes.
“Our findings that small molecule agonists of leukocyte-specific integrins can reduce inflammatory injury suggests that integrin activation could be a potential new mechanism for the discovery of novel therapeutics against other diseases where cell motility and integrin function play a key role,” said Gupta, the senior author. “Almost every cell in our body contains integrins, and we believe that other integrins can similarly be targeted with small molecule based integrin agonists.”
Leukocytes are important immune cells that normally circulate in the blood vessels. When an injury or infection occurs, the leukocytes adhere to the blood vessel walls and then migrate out of the vessels into the damaged tissue—among the first cells to do so to help repair wounds and fight off infections.
In some cases, however, too many white blood cells are recruited to fight an injury, leading to inflammatory and autoimmune diseases. It’s at this point that the family of integrins on the surface of white blood cells mediates their adhesion, migration and recruitment into injured or inflamed tissue. Through a blocking process, integrins can be prevented from adhering to the blood vessel walls, thus reducing the number of cells accumulating in the inflamed tissue. Still, the use of blockers (antagonists) has been unsuccessful as a treatment for a majority of inflammatory and autoimmune diseases.
The new research takes the opposite approach—increasing integrin-mediated cell adhesion—and found it to be an even more effective strategy for reducing the recruitment of white blood cells and tissue inflammation. While counter-intuitive, as cell adhesion is a prerequisite for the transmigration of white blood cells out of the blood vessels, the findings show that enhancing cell adhesion with small molecule agonists also significantly reduces their migration out of the blood vessels and can be more effective in treating certain inflammatory diseases as compared to antagonists.
“Having seen this project developing step-wise from concept, chemical screen and molecular-biological evaluation to what it is today—a novel therapeutic compound with large potential—is particularly rewarding for me,” said study co-author Jochen Reiser, M.D., Ph.D., professor and vice chair for research in the Department of Medicine, chief of the Division of Nephrology and Hypertension, and director of the Peggy and Harold Katz Family Drug Discovery Center.
In addition to Drs. Gupta and Reiser, the multidisciplinary research was conducted by 10 others from UM: from the Division of Nephrology and Hypertension, Dony Maiguel, Ph.D., and Mohd Hafeez Faridi, Ph.D., postdoctoral associates, Changli Wei, M.D., Ph.D., assistant professor of medicine, Ali Nayer, M.D., assistant professor of medicine, and technicians Constantinos J. Barth and Mary Donnelly.
Participating from the DeWitt Daughtry Family Department of Surgery were Dayami Hernandez, a histotechnologist, Phillip Ruiz, M.D., Ph.D., professor of surgery and medical director of transplant laboratories, and Roberto I. Vazquez-Padron, Ph.D., research assistant professor of surgery at the Vascular Biology Institute. The Center for Computational Science’s Stephan Schürer, Ph.D., research assistant professor of molecular and cellular pharmacology, also contributed.
Six researchers from outside the Miller School also were involved.