A collaborative team of researchers led by Lerner Research Institute has published a new study in Immunity that offers key insights into how steroids function to control inflammatory diseases. The findings provide evidence of the vital role of regulatory T (Treg) cells in regulating inflammatory disorders such as asthma, multiple sclerosis and experimental autoimmune encephalomyelitis.
Glucocorticoids (GC) are the mainstay treatment option for inflammatory conditions. The anti-inflammatory benefits take effect when GCs bind to cellular receptors found in every cell in our body. Although these steroids were discovered approximately 70 years ago and are broadly used to control chronic inflammation, the specific mechanisms that mediate these benefits have remained elusive.
Booki Min, DVM, PhD, staff member in the Department of Inflammation & Immunity and lead author on the study, and his team show here that GC receptor binding on Treg cells—a type of immune-suppressing cell that helps to control inflammation—is especially important. In this class of cells, GCs induce a microRNA-mediated signaling cascade that ultimately results in the anti-inflammatory drug benefits through Treg cells.
“Resistance to steroids, like GCs, is unfortunately common in a host of chronic inflammatory diseases. While they may provide relief for patients initially, they eventually become ineffective as cells learn to adapt and become refractory to the treatment,” said Dr. Min. “Our study importantly identifies some downstream targets of GCs, which we may be able to target to treat GC-resistant disease.”
Previous studies from Dr. Min’s laboratory revealed that Treg cell dysregulation is common in many chronic inflammatory conditions.
miRNA-342: a crucial downstream target
In the current study, researchers discovered that GC receptors on these cells are paramount in treatment response. When GC receptor binding on Treg cells was abolished in preclinical models, GC-mediated immune suppression was lost and failed to control inflammation.
Researchers also found that dexamethasone (a prescribed corticosteroid) induced a signaling cascade that involved two key players—the microRNA miRNA-342 and a protein called Rictor (rapamycin-insensitive companion of mammalian target of rapamycin). When researchers overexpressed miRNA-342, they importantly observed that Treg cell function was enhanced—that is, better suppressed inflammation—even in the absence of dexamethasone.
“Our findings suggest that after the initial benefits of GC treatment wane and cells become resistant, we may be able to target other molecules in the GC-Treg cell pathway, like miRNA-342, to help treat patients whose inflammatory disorders have become more aggressive,” said Dr. Min.
While additional research will be necessary, these findings lay the groundwork for an entirely new treatment approach for steroid-resistant inflammatory diseases.
This study was supported in part by the National Institutes of Health and the Multiple Sclerosis Society. Dongkyun Kim, PhD, a postdoctoral research fellow in the Min laboratory, was first author on the study.
Images: Rendering of a regulatory T cell (top); detailed GC-Treg cell signaling pathway (bottom)