Long 3′UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation 2023 Dorrity et al

Editor’s summary
The central nervous system relies on pattern recognition receptors (PRRs) to trigger innate immune responses against neurotropic viruses, but excessive PRR activation can also contribute to neurodegenerative diseases. Dorrity et al. found that human neurons express particularly high levels of long double-stranded RNAs (dsRNA) that activate PRRs, leading to constitutive production of type I interferon (IFN-I). The ELAV-like RNA-binding proteins HuB and HuC generated elongated 3’ untranslated regions (UTRs) that gave rise to neuronal dsRNA structures. Loss of HuB and HuC increased susceptibility to herpes simplex virus 1 and Zika virus infection in wild-type neurons but improved survival of neurons lacking ADAR1, the gene mutated in Aicardi-Goutières syndrome. Together, these results identify elongated 3’UTRs as a source of immunostimulatory dsRNA in neurons that couples antiviral responses with pathological inflammation. —Claire Olingy

Abstract
Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded RNA (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types.

Here, we report that human neurons intrinsically carry exceptionally high levels of immunostimulatory dsRNAs and identify long 3′UTRs as giving rise to neuronal dsRNA structures. We found that the neuron-enriched ELAVL family of genes (ELAVL2, ELAVL3, and ELAVL4) can increase (i) 3′UTR length, (ii) dsRNA load, and (iii) activation of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3. In wild-type neurons, neuronal dsRNAs signaled through PRRs to induce tonic production of the antiviral type I interferon.

Depleting ELAVL2 in WT neurons led to global shortening of 3′UTR length, reduced immunostimulatory dsRNA levels, and rendered WT neurons susceptible to herpes simplex virus and Zika virus infection. Neurons deficient in ADAR1, a dsRNA-editing enzyme mutated in the neuroinflammatory disorder Aicardi-Goutières syndrome, exhibited intolerably high levels of dsRNA that triggered PRR-mediated toxic inflammation and neuronal death. Depleting ELAVL2 in ADAR1 knockout neurons led to prolonged neuron survival by reducing immunostimulatory dsRNA levels.

In summary, neurons are specialized cells where PRRs constantly sense “self” dsRNAs to preemptively induce protective antiviral immunity, but maintaining RNA homeostasis is paramount to prevent pathological neuroinflammation.

Paywall, https://www.science.org/doi/10.1126/sciimmunol.adg2979

 

NIH Director's Blog.

How Double-Stranded RNA Protects the Brain Against Infection While Making Damaging Neuroinflammation More Likely

"When you get a run-of-the-mill viral infection, after a few days of symptoms your immune system typically fends off the bug, and you’ll make a full recovery. In rare cases, a virus can infect the brain. This can lead to much bigger problems, including cognitive impairments known as “brain fog,” other neuropsychiatric symptoms, potentially irreversible brain damage, or even death. For this reason, the brain, more than other parts of the body, relies heavily on immune responses that can control viral infections immediately.

Now some intriguing findings from an NIH-funded team reported in Science Immunology help to explain how the brain is protected against infections.1 However, the findings also highlight a serious downside: these same mechanisms that protect the brain also leave it especially vulnerable to damaging levels of neuroinflammation."

https://directorsblog.nih.gov/2023/...aking-damaging-neuroinflammation-more-likely/

 

This may help understand why brainfog occurs from non-viral causes. ME could involve this mechanism even without a viral infection.

This is also the kind of brain function affecting factor that probably hasn't been looked for in the various serum or even CSF samples. Looking for a few factors that are easy to find in common head injuries or infections is not enough. This is also why I have little hope of "looking for factors in serum or CSF" studies finding the cause of ME: there are just too many still unknown factors, and too many that may be highly localized or which have very short half-lives. There are probably other factors that are simply ignored because "we (wrongly) understand that fully, so no need to pay attention to it".