Researchers have discovered that the chronic activation of a molecule that acts as a metabolic sensor in mice may be the driving force behind sarcoidosis development. Since there are approved drugs that act on the molecule, it will be possible to quickly determine whether the treatment also works in humans.
The study, “Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression,” was published in the journal Nature Immunology.
Until now, scientists have been in the dark about why specific immune cells, called macrophages, sometimes cluster together in the granulomas characteristic of sarcoidosis. By exploring molecular factors in these cells, a research team at the Medical University Vienna discovered that the chronic activation of one molecule was enough to trigger the development of sarcoidosis in laboratory animals.
The factor, called mTOR (mammalian target of rapamycin), acts as a sensor that measures the availability of various nutrients and adapts cell metabolism accordingly. When this molecule is chronically activated in macrophages, they swell up, start dividing uncontrollably, and gather in clusters.
“We discovered that the chronic activation of the mTOR protein directly in macrophages is enough to form spontaneous granulomas in many tissues in the animal model,” Monika Linke, PhD student and lead author of the study, said in a press release.
Additional evidence was provided when researchers blocked mTOR in the laboratory animals. When mTOR was no longer signaling, the activation of cell death pathways rapidly cleared the granulomas from the mice tissue.
Based on the finding, the research team went on to explore granulomas in patients. “We discovered that, especially in the progressive form of sarcoidosis, mTOR is also active and leads to progression of the disease,” said Thomas Weichhart, research group leader at the Institute of Medical Genetics of the Medical University of Vienna.
And soon, they may reveal whether compounds that block mTOR — used in cancer treatment and transplant medicine — are able to treat human sarcoidosis. The team has already initiated a clinical trial exploring if such treatment is equally helpful in humans as it is in mice.
“This once again underscores the importance of basic research and shows how quickly some findings can be transferred to patients,” Weichhart concluded.