Blocking AhR Sensor Activates Regenerative Program in Injured Neurons

A molecular switch in neurons regulates the regrowth of damaged axonal fibers. This is according to findings in mice, published in a new Nature paper titled “AhR inhibition promotes axon regeneration via a stress–growth switch, that show that blocking a protein called the aryl hydrocarbon receptor (AhR) may help neural regeneration and restore function after injuries to the peripheral nerves or spinal cords. The work is led by a team of scientists from the Icahn School of Medicine at Mount Sinai and their collaborators at other institutions. 

It is an important piece to the puzzle of why neurons in adult mammals have a limited ability to regrow damaged axonal connections. Because of this limitation, injuries to the nerves or spinal cord often result in permanent loss of movement or sensation. “When neurons are injured, they must deal with stress while also trying to regrow their axons,” explained Hongyan Zou, MD, PhD, a professor of neurosurgery, and neuroscience, at the Icahn School of Medicine at Mount Sinai and the study’s senior author. AhR, which was originally identified as a xenobiotic sensor that detects environmental toxins and pollutants, appears to integrate environmental sensing and regenerative capabilities to regrow axons after injury. 

As the scientists explain in Nature, “our work establishes AhR as a brake on axon regeneration that integrates transcriptional, metabolic and epigenetic programs to enforce proteostasis at the expense of regenerative growth.” Basically it “functions like a brake that shifts neurons toward managing stress rather than rebuilding damaged connections,” Zou said. 

According to results reported in the paper, the team found that when AhR signaling is active, axon growth slows. But when the protein is removed from neurons or has its signaling activity blocked with drugs, axonal fibers grew more effectively. In fact, in mouse models of peripheral nerve injury and spinal cord injury, inhibiting AhR also improved recovery of motor and sensory function, the scientists wrote. 

More detailed experiments helped elucidate how the process works. Following injury or stress, AhR helps neurons cope by maintaining proteostasis and reducing the protein production needed for growth. When it is turned off, neurons adopt a new protection strategy. They begin producing more protein and activate growth-related pathways that support axon regeneration. The growth process is also supported by HIF-1α, which helps regulate genes involved in metabolism and tissue repair. 

These results point to some possible treatment directions for spinal cord injury, stroke, or other neurological diseases. Several drugs that block AhR are already being tested in clinical trials for other diseases, and they could eventually be studied in this context as well. However, more research is needed before this approach can be trialed in patients, the scientists said. 

Future studies will examine how effective AhR inhibitors are in different types of neural damage, determine the best timing and dosage for treatment, and assess the impact of these treatments on other cells after injury. As part of their next steps, the Mount Sinai team plans to test AhR-blocking drugs and gene-therapy strategies designed to reduce the protein’s activity in neurons. 

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