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Genetic or Pharmacological Induction of the Hypoxia Response Enhances Functional Regeneration Following Peripheral Nerve Injury

Peripheral nerve injuries (PNIs) occur in 1–3% of patients with traumatic injuries. While peripheral axons have the ability to regenerate at ~1mm/day, the distance over which they must do so means lengthy recovery times, which are associated with regenerative failure due to a decline in supporting cells' ability to maintain axon growth. Successful axonal regeneration depends heavily upon the neuronal response to injury, as well as that of myeloid cells recruited to the damaged nerve. In injured neurons, transcriptomic changes occur which mirror those observed in hypoxia. Hypoxia inducible factors (HIFs) effect these transcriptomic changes; these are governed in turn by prolyl hydroxylase domain (PHD) proteins. Under normoxic conditions, PHDs act as master regulators of the hypoxia response, targeting HIFs for proteasomal degradation. We hypothesize that deleting any or all of the PHDs (PHD1, 2, and 3), or inhibiting PHDs pharmacologically, will induce the hypoxia response and enhance axonal regeneration and functional recovery following PNI. We used global PHD1 knockout, global PHD3 knockout, and heterozygous PHD2 transgenic mice, as well as non‐transgenic mice treated with DMOG, a pan‐PHD inhibitor. We used a sciatic nerve crush model of injury and assessed functional recovery at various time points post‐injury using toe pinch and grasping tests, and electromyography. Using immunohistochemistry we characterized macrophage and axon densities in the nerves after injury. We also assessed DMOG‐induced changes in macrophage phenotype using FACS, RT‐PCR and immunohistochemistry. We found that deletion of PHD1 or PHD3, or inhibition of all three PHDs resulted in earlier functional recovery after injury, increased macrophage infiltration in the injured nerve, an M2‐skewed macrophage phenotype, and enhanced axonal regrowth. In addition, deletion of any of the PHDs, or their inhibition by DMOG, resulted in improved electromyographical responses of the nerve one month post injury. Our findings suggest that functional recovery after peripheral nerve injury can be aided by hypoxia‐independent induction of the hypoxia response.