Massachusetts General Hospital (MGH) researchers – along with collaborators from Massachusetts Institute of Technology (MIT) and Alnylam Pharmaceuticals – have found a way to block, in an animal model, the damaging inflammation that contributes to many disease conditions.
In their report receiving early online publication in Nature Biotechnology, the investigators describe using small interfering RNA technology to silence the biochemical signals that attract a particular group of inflammatory cells to areas of tissue damage.
"The white blood cells known as monocytes play a critical role in the early stages of the immune response," says Matthias Nahrendorf, MD, PhD, of the MGH Center for Systems Biology, the paper's senior author. "We now know there are two subsets of monocytes – an inflammatory subset that defends against pathogens and a reparative subset that supports healing. But if the inflammatory response is excessive, it can block the healing process and exacerbate conditions such heart disease and cancer."
Cells damaged by injury or disease release a cocktail of chemicals called cytokines that attract immune cells to the site of the damage. Inflammatory monocytes are guided to sites of tissue injury by a receptor protein called CCR2, and the MGH-led team devised a strategy targeting that molecule to block the inflammatory process but not the action of the reparative monocytes.
Small interfering RNA (siRNA) technology prevents production of specific proteins by binding to associated messenger RNA molecules and preventing their translation. Because the technique requires extreme precision in developing the right siRNA molecule and delivering it to the correct cellular location, the MGH team collaborated with Alnylam scientists who are experts in RNA-interference-based therapeutics and with MIT investigators Robert Langer, ScD, and Daniel Anderson, PhD, who have developed a nanoparticle-based system for delivering molecules to specific cellular compartments.
To make sure that their siRNA preparation targeted the right monocytes, the investigators first confirmed that its use reduced levels of CCR2 in monocytes and increased levels of the fragments produced when siRNA binds to its target. They then showed that monocytes from mice treated with the siRNA preparation were unable to migrate towards CCR2's usual molecular target. Experiments in animal models of several important diseases showed that the siRNA preparation reduced the amount of cardiac muscle damaged by a heart attack, reduced the size and the number of inflammatory cells in atherosclerotic plaques and in lymphomas, and improved the survival of transplanted pancreatic islets.
"These inflammatory monocytes are involved in almost every major disease," Nahrendorf explains. "Anti-inflammatory drugs currently on the market hit every inflammatory cell in the body, which can produce unwanted side effects. This new siRNA treatment doesn't affect inflammatory cells that don't rely on the CCCR2 receptor. That makes a big difference." Nahrendorf is an assistant professor of Radiology at Harvard Medical School.
Florian Leuschner and Partha Dutta of the MGH Center for Systems Biology are co-lead authors of the paper. Additional co-authors are Rostic Gorbatov, Jessica Donahoe, Gabriel Courties, Brett Marinelli, Yoshiko Iwamoto, Virna Cortez-Retamozo, Andita Newton, Mikael Pittet, Filip Swirski and Ralph Weissleder, MGH Center for Systems Biology; Tatiana Novobrantseva, Stuart Milstein, Hila Epstein-Barash, William Cantley, Jamie Wong, and Victor Koteliansky, Alnylam Pharmaceuticals; Kang Mi Lee, James Kim and James Markmann, MGH Department of Surgery; Peter Panizzi, Auburn University; Won Woo Lee, Seoul National University; Kevin Love, Massachusetts Institute of Technology; and Peter Libby, Brigham and Women's Hospital. The study was supported by grants from the National Institute of Health and other funders.
Celebrating the 200th anniversary of its founding in 1811, Massachusetts General Hospital (www.massgeneral.org) is the original and largest teaching hospital of Harvard Medical School. MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $700 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.
Sue McGreevey | EurekAlert!
Scientists spin artificial silk from whey protein
24.01.2017 | Deutsches Elektronen-Synchrotron DESY
Choreographing the microRNA-target dance
24.01.2017 | UT Southwestern Medical Center
A Swedish-German team of researchers has cleared up a key process for the artificial production of silk. With the help of the intense X-rays from DESY's...
For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.
According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
24.01.2017 | Physics and Astronomy
24.01.2017 | Life Sciences
24.01.2017 | Health and Medicine