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!
Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg
The balancing act: An enzyme that links endocytosis to membrane recycling
07.12.2016 | National Centre for Biological Sciences
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
08.12.2016 | Materials Sciences
08.12.2016 | Materials Sciences
08.12.2016 | Physics and Astronomy