A newly discovered mechanism protects tissues from TNF-driven immune pathology by limiting receptor abundance

Inflammation is a protective immune mechanism that is triggered when we are injured or infected, but excessive or chronic inflammation damages tissues and leads to inflammatory pathologies such psoriasis and inflammatory bowel disease. This raises a central question: how do tissues withstand inflammation during an immune response?

To address this, we studied the regulation of the immune receptor TNFR1 which is activated by tumour necrosis factor (TNF), a key cytokine that orchestrates inflammatory responses. Our study identifies an evolutionarily conserved small regulatory element within the TNFR1 mRNA known as an upstream open reading frame (uORF). This short sequence acts like a molecular brake on the protein production of TNFR1, limiting how much TNFR1 is made and thereby limits the signalling response of cells to TNF. 

Using a new mouse model in which one of two uORFs in the gene encoding TNFR1 is mutated, we show that increased abundance of TNFR1 leads to acute tissue damage of multiple organs, including the liver, skin, intestines, when mice are challenged with doses of TNF that is well-tolerated by animals with normal TNFR1 levels. We further reveal that the uORF-dependent control of TNFR1 production is regulated by cellular stress conditions such as low oxygen, ultraviolet radiation, or inflammatory signals. This allows cells to fine-tune their inflammatory sensitivity based on their condition, linking environmental stress directly to immune responsiveness.

Finally, we provide evidence that the translation of other immune receptor mRNAs, including TLR4, IFNAR1, and IFNGR2, is also controlled by uORFs, suggesting that this is a general mechanism by which excessive immune responses and subsequent tissue damage may be controlled.

Further investigation of uORF-mediated control of immune receptor abundance may ultimately help guide new strategies to manage inflammatory diseases, not by blocking immune reactions entirely, but by helping tissues better tolerate it.

The full article can be viewed here: https://www.science.org/eprint/T6FPQYQRVWMQ589MKTPY/full?activationRedirect=/doi/full/10.1126/sciimmunol.aeb6484.