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Mass. Eye and Ear researchers describe the role of endomucin, a molecule that – under healthy circumstances – resists the adhesion of white blood cells as they move through the circulatory system. These findings suggest that promoting the expression of endomucin may prevent the collection of white blood cells that causes tissues to become inflamed.
Researchers from the Harvard Medical School (HMS) Department of Ophthalmology and the Schepens Eye Research Institute of Massachusetts Eye and Ear have gained new insight into how a non-inflammatory state is maintained in the body. Their work focuses on the role of endomucin, a key molecule with anti-adhesive properties that encourages neutrophils – prevalent white blood cells that sense signals of injury — to travel past the vascular endothelium. Their findings, published in the current issue of Nature Communications
, represent a paradigm shift in our understanding of inflammation.
Blood cells move through the circulatory system from the heart through the arteries to the smallest capillaries, and then to the veins and back to the heart. The vascular system is lined with the endothelium, a thin layer of cells that serve as an interface between the blood and the tissues. When there is an injury or disease process, the body sends out signals that recruit circulating neutrophils to stick to the endothelium; the neutrophils then migrate between the endothelial cells to and pass into tissue. The accumulation of neutrophils and other white blood cells in the injured tissues is facilitated an increase in adhesive molecules on the surface of the small vessels in injured tissue.
The research, led by Drs. Patricia D’Amore
, Charles L. Schepens Professor of Ophthalmology and Pablo Argüeso
, Associate Professor of Ophthalmology, both at Harvard Medical School, shows that in healthy, non-inflamed tissue, endomucin plays a critical role in preventing the neutrophils from sticking to the endothelium. During inflammatory conditions, however, the endomucin on the endothelial cell surface is dramatically reduced and the levels of pro-adhesives molecules (such as ICAM) on the endothelium increase, resulting in neutrophil accumulation. The researchers showed both in tissue culture and animal models that the adherence and infiltration of inflammatory cells could be blocked by experimentally expressing excess endomucin in the vascular endothelium.
“Until now researchers studying the role of the endothelium in inflammation have primarily focused on pro-adhesive molecules that trap the white blood cells at the site of injury,” said Pablo Argüeso, Ph.D. “We have now shown that there is also a mechanism to maintain an anti-adhesive surface on the vascular endothelium. Endomucin acts to prevent the inflammatory cells from adhering to blood vessels. The fact that endomucin decreases during inflammation suggests that this molecule may be as important in transforming the endothelial cell surface to a proinflammatory state as the elevation in adhesive molecules.”
Most current treatments for inflammation involve targeting the activities of cytokines and inflammatory mediators, which have risks and limitations. This new knowledge may be used to develop treatments for inflammation by promoting the expression of endomucin to prevent the movement of inflammatory cells from the capillaries into inflamed tissues.
“In our experiments, we have shown that there is potential to interfere with inflammation by promoting the expression of endomucin,” said Dr. Argüeso. “Many diseases have an inflammatory component, and by targeting this molecule, we believe we can reduce unnecessary inflammation.”
Additional co-authors of the Nature Communications paper include Alisar Zahr, Pilar Alcaide, Jinling Yang, Alexander Jones, Meredith Gregory, Nathanial G. dela Paz, Sunita Patel-Hett, Tania nevers, Francis W. Luscinskas, Magali Saint-Geniez and Bruce Ksander of Massachusetts Eye and Ear/ Schepens Eye Research Institute and the Department of Ophthalmology at Harvard Medical School.
This study was supported by the Schepens Eye Research Institute Co-Investigative Pilot Project Initiative (P.A.D. and P.Ar.), National Eye Institute Grants EY014847 (P.Ar.) and EY05318 (P.A.D.), and National Heart, Lung and Blood Institute Grants HL036028 (F.W.L.), HL094706 (P.Al.) and HL123658 (P.Al.).
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Mass. Eye and Ear clinicians and scientists are driven by a mission to find cures for blindness, deafness and diseases of the head and neck. Now united with Schepens Eye Research Institute, Mass. Eye and Ear is the world's largest vision and hearing research center, developing new treatments and cures through discovery and innovation. Mass. Eye and Ear is a Harvard Medical School teaching hospital and trains future medical leaders in ophthalmology and otolaryngology, through residency as well as clinical and research fellowships. Internationally acclaimed since its founding in 1824, Mass. Eye and Ear employs full-time, board-certified physicians who offer high-quality and affordable specialty care that ranges from the routine to the very complex. U.S. News & World Report’s “Best Hospitals Survey” has consistently ranked the Mass. Eye and Ear Departments of Otolaryngology and Ophthalmology as top in the nation. For more information about life-changing care and research, or to learn how you can help, please visit MassEyeAndEar.org.