Newly discovered inflammatory cell signaling could open the door to autoimmune disease treatments
· Medical Xpressedited by Sadie Harley, reviewed by Robert Egan
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Our understanding of how cells interact with each other has been driven for decades by the central concept of receptor-mediated signal transduction. Now, researchers from Boston Children's Hospital are reporting the discovery of a new, receptor-free means of signal transduction.
This discovery not only suggests alternative pathways for cell-to-cell communication but also identifies a potentially more effective therapeutic target for treating autoimmune diseases. Their results are published in Nature.
"The discovery of this receptor-free signal transduction underscores the value of exploratory science as a means to expand the lexicon of life," said Jonathan Kagan, Ph.D., senior author and director of basic research and Shwachman Chair in Gastroenterology at Boston Children's.
Signals released from receptors
All human disease is driven by changes in cell function, and these changes are driven by the actions of receptors. Receptor-mediated signal transduction posits that receptors detect changes in the environment (e.g., other cells, infections, cancers) and, once detected, bind to cytoplasmic proteins that signal changes in cell function, such as inflammation.
Kagan and his team observed a different process in which Toll-like receptors (TLRs)—the guardians of our immune system—assembled but then released signaling proteins during inflammation. Yet, contrary to dogma, the release of these signaling proteins did not stop the inflammatory process.
Rather, the receptor-free state of these signaling proteins was necessary to assemble a key inflammation-stimulatory organelle called the myddosome. Without receptor release, myddosomes could neither form nor induce inflammatory gene expression.
Targeting the myddosome instead
The ability of cells to instigate functional changes without receptors acting as the middleman has exciting implications at both the scientific and clinical levels. Since the Nobel Prize–winning discovery of TLRs as drivers of inflammation and immunity in the 1990s, scientists have worked to develop therapies that suppress TLR activity by interfering with receptors, with little success.
The discovery of receptor-free signal transduction provides an explanation as to why receptors cannot be the therapeutic target. With this new research, Kagan believes the myddosome may be a more effective target.
"New strategies to manipulate the TLR pathway, central to so many aspects of inflammation, are now possible," said Kagan.
"We have already found pharmacological evidence that disruption of myddosomes (rather than receptor function) resolved inflammation in mice. Our hope is to develop new classes of small molecules that manipulate myddosomes as a means of therapeutic treatment for autoimmune diseases and beyond."
Publication details
Jonathan Kagan, TRAM promotes Toll-like-receptor-free myddosome signal transduction, Nature (2026). DOI: 10.1038/s41586-026-11052-y. www.nature.com/articles/s41586-026-11052-y
Journal information: Nature
Key medical concepts
Toll-Like ReceptorsInflammationAutoimmune Diseases
Clinical categories
Allergy and immunology Provided by Children's Hospital Boston Who's behind this story?
Sadie Harley
BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →
Robert Egan
Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →
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