Discovery of receptor-free signaling reveals better targets for treating autoimmune diseases

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 today in Nature.

The discovery of this receptor-free signaling transduction underscores the value of exploratory science as a means to expand the lexicon of life."

Jonathan Kagan, PhD, senior author and Director of Basic Research and Shwachman Chair in Gastroenterology, Boston Children's

All human disease is driven by changes in cell functions, 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 to induce changes in cell function, such as inflammation.

Kagan and his team observed a different process wherein Toll-like Receptors (TLRs) – the guardians of our immune system – assembled but then released signaling proteins during the process of 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 not form nor induce inflammatory gene expression.

The ability for cells to instigate functional changes without receptors acting as the middleman has exciting implications at both the scientific and clinical level. Since the Nobel Prize-winning discovery of TLRs as the driver 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 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 disrupting 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."