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In a recent study, researchers lead by Professor Kim Midwood at the Kennedy Institute of Rheumatology shed light on how endogenous triggers of inflammation are recognised by immune sensors.

Human health depends on our ability to detect and respond to everyday threats including exposure to infection or tissue injury. We do this using a group of molecular sensors that can detect danger. These sensors are triggered by motifs found in harmful bacteria or viruses, causing the activation of an immune response to fight pathogen invasion. These sensors can also be triggered by molecules generated in the body as a result of tissue damage, and these signals activate an immune response that destroys injured tissue and repairs damage.

It is important to control how much of these internal danger signals are present in the body; whilst they are essential for protecting us from tissue injury, if high levels accumulate this can lead to chronic inflammation, causing inappropriate immune responses that attack healthy tissues. However, how these molecules act, what controls them, and how this goes wrong during disease, is still very poorly understood.

Investigating toll-like receptor 4 (TLR4), a key immune sensor, and tenascin-C, a molecule generated upon tissue damage, the research team identified the exact sites exposed on the surface of tenascin-C that are responsible for triggering activation of TLR4. 

Examination of a wide range of diverse proteins that contain similar motifs revealed that these molecules also act as danger signals by activating TLR4. Tenascin-C, and many of these newly discovered danger signals, are known to drive inflammation in autoimmune diseases such as rheumatoid arthritis, in fibrotic diseases and in aggressive or metastatic tumours.


This work highlights how these molecules might contribute to disease, and our understanding of the structural details behind immune sensor activation now enables the design of drugs that can effectively block their activity. 

You can read the full article Nature Communications:

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