Scientists Discover a Hidden Trigger That Keeps Inflammation Alive

Inflammation persists after proteins detach from immune receptors, revealing a potential target for autoimmune treatments.

Since a Nobel Prize-winning discovery in the 1990s identified molecules called Toll-like Receptors as the guardians of the human immune system, researchers have pursued a straightforward strategy for treating autoimmune diseases. By developing therapies that interfere with these receptors, scientists hoped to suppress runaway inflammation. Yet those efforts have seen little success.

Research from Boston Children’s Hospital suggests that a crucial part of the inflammatory response depends on what happens after signaling proteins separate from those receptors. The team found that the proteins had to break free before they could assemble a structure that activates inflammatory genes. Published September 23, 2026, in Nature, the study points to that structure as a potentially more effective treatment target for autoimmune diseases.

Inflammation persists beyond the receptor

To understand why that separation matters, consider how receptors are generally thought to work. They detect changes around a cell, including signals associated with other cells, infections, or cancer, and bind to signaling proteins in the cytoplasm, the cell’s interior. Those proteins then prompt changes in cell function, such as inflammation. This process, called receptor-mediated signal transduction, has shaped scientists’ understanding of cell communication and the changes in cell behavior that drive disease.

The Boston Children’s team observed the familiar beginning of that process, with Toll-like receptors bringing signaling proteins together. But the receptors then released the proteins, and inflammation continued. Under the conventional model, losing the connection to the receptor should have stopped the inflammatory signaling.

Instead, being released allowed the proteins to assemble an organelle called the myddosome, a structure within the cell that stimulates inflammation. The separation was essential to its formation. Without release from the receptors, myddosomes could not form or activate inflammatory genes. The receptors therefore helped initiate the process, but the proteins needed to leave them behind to carry out this later step.

Jonathan Kagan, PhD, the study’s senior author and director of basic research and Shwachman Chair in Gastroenterology at Boston Children’s, described the finding as an expansion of the ways scientists understand cellular signaling.

“The discovery of this receptor-free signaling transduction underscores the value of exploratory science as a means to expand the lexicon of life,” said Kagan.

Myddosomes could offer a better treatment target

The distinction between starting the response and assembling its inflammatory machinery could help explain why treatments aimed at Toll-like receptors have struggled. Kagan believes targeting the myddosome itself may offer a more effective way to intervene, and the team has evidence from drug experiments in mice to support pursuing that approach.

“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.”

Reference: “TRAM promotes Toll-like-receptor-free myddosome signal transduction” by Daniel Fisch, Vaani Ohri, Eleni Anastasakou, Lucia J. Wesemann, Joon H. Choi, Katherine E. Lindblad and Jonathan C. Kagan, 23 September 2026, Nature.
DOI: 10.1038/s41586-026-11052-y