Reduced White Matter Damage and Lower Neuroinflammatory Potential of Microglia and Macrophages in Hri/Eif2ak1^-/- Mice After Contusive Spinal Cord Injury

Cellular stressors inhibit general protein synthesis while upregulating stress response transcripts and/or proteins. Phosphorylation of the translation factor eIF2α by one of the several stress-activated kinases is a trigger for such signaling, known as the integrated stress response (ISR). The ISR regulates cell survival and function under stress. Here, germline knockout mice were used to determine contributions by three major ISR kinases, HRI/EIF2AK1, GCN2/EIF2AK4, and PKR//EIF2AK2, to pathogenesis of moderate contusive spinal cord injury (SCI) at the thoracic T9 level. One-day post-injury (dpi), reduced levels of peIF2α were found in Hri^-/- and Gcn2^-/-, but not in Pkr^-/- mice. In addition, Hri^-/- mice showed attenuated expression of the downstream ISR transcripts, Atf4 or Chop. Such differential effects of SCI-activated ISR correlated with a strong or moderate enhancement of locomotor recovery in Hri^-/- or Gcn2^-/- mice, respectively. Hri^-/- mice also showed reduced white matter loss, increased content of oligodendrocytes (OL) and attenuated neuroinflammation, including decreased lipid accumulation in microglia/macrophages. Cultured neonatal Hri^-/- OLs showed lower ISR cytotoxicity. Moreover, cell autonomous reduction in neuroinflammatory potential was observed in microglia and bone marrow-derived macrophages derived from Hri^-/- mice. These data identify HRI as a major positive regulator of SCI-associated secondary injury. In addition, targeting HRI may enable multimodal neuroprotection to enhance functional recovery after SCI.