An international multi-disciplinary research team led by Northwestern Medicine scientists has uncovered a new role for the protein toll-like receptor 4 (TLR4) in the development of tissue fibrosis, or scarring.
This finding, recently reported in the American Journal of Pathology, has implications for the treatment of scleroderma, a condition for which there currently is no effective treatment.
TLR4 was previously implicated in inflammation, but its role in tissue fibrosis was unknown. Fibrosis is a hallmark of scleroderma and contributes to a range of common diseases including pulmonary fibrosis, kidney fibrosis, liver cirrhosis and radiation-induced scarring.
"We found that when the gene for TLR4 was mutated in mice, the mice became resistant to experimental scleroderma," said the study's first author Swati Bhattacharyya, research assistant professor of rheumatology at Northwestern University Feinberg School of Medicine. "Moreover, scleroderma patients showed abnormal TLR4 levels in fibrotic skin and lung tissue. This tells us we have found a therapeutic target."
Scleroderma is a chronic autoimmune disease which causes progressive tightening of the skin and can lead to serious internal organ damage and, in some cases, death. Scleroderma affects an estimated 300,000 people in the U.S., most frequently young-to-middle-aged women. Its cause and pathogenesis are unknown.
"The Northwestern research team continues to make fundamental discoveries that enhance our scientific understanding of scleroderma," said co-author John Varga, M.D., the John and Nancy Hughes Distinguished Professor of Rheumatology and professor of dermatology at Feinberg. "Careful dissection of the role of individual proteins in this disease enables us to make real progress toward novel treatments."
Researchers from Northwestern, Boston University, the University of Pittsburgh and the University Medical Center Nijmegen, Netherlands contributed to the study, which relied on tissue samples from human scleroderma patients and mouse models.
Agents that block TLR4 are already being developed for inflammation and sepsis in humans. Effective TLR4 inhibitor drugs may blunt and even possibly reverse the fibrosis in scleroderma, says Bhattacharyya. However, earlier attempts to develop therapeutics that block TLR4 have met with failure due to toxicity.
"These results, while significant, are preliminary. We now know that TLR4 plays a role in scleroderma, but much research remains to be done to develop safe and effective drugs to inhibit this pathway," she says.
The investigators are currently studying additional mouse models to better understand the role of TLR4 in fibrosis and are developing novel small molecules to selectively block TLR4 as a potential therapy.
This study was supported by grant AR-42309 from The National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.
Kathleen Kelley, Denisa Melichian, Zenshiro Tamaki, Feng Fang, Gilbert Feng, Richard Pope, Scott Budinger, and Gokhan Mutlu from Feinberg also contributed to the research.
Marla Paul | EurekAlert!
Two Group A Streptococcus genes linked to 'flesh-eating' bacterial infections
25.09.2017 | University of Maryland
Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden
At the productronica trade fair in Munich this November, the Fraunhofer Institute for Laser Technology ILT will be presenting Laser-Based Tape-Automated Bonding, LaserTAB for short. The experts from Aachen will be demonstrating how new battery cells and power electronics can be micro-welded more efficiently and precisely than ever before thanks to new optics and robot support.
Fraunhofer ILT from Aachen relies on a clever combination of robotics and a laser scanner with new optics as well as process monitoring, which it has developed...
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
25.09.2017 | Trade Fair News
25.09.2017 | Physics and Astronomy
25.09.2017 | Life Sciences