Deletion of Endoplasmic Reticulum Stress-Induced CHOP Protects Microvasculature Post-Spinal Cord Injury

Abstract

Trauma introduces damaging stressors that compromise protein, lipid, and nucleic acid integrity. Aggregates of unfolded and misfolded proteins in the endoplasmic reticulum (ER) triggers the ER stress response (ERSR)/unfolded protein response (UPR) leading to activation of three signaling pathways mediated by PERK, ATF6, and IRE1. Initially, the ERSR/UPR is pro-homeostatic as it globally slows translation while increasing translation of chaperone proteins and inducing ER-associated degradation. If the cellular stress is not controlled, apoptosis is subsequently induced through several mechanisms, of which the most well-described is CHOP. Following spinal cord injury (SCI), mice deficient in CHOP signaling show increased spared white matter and enhanced locomotor recovery by 6 weeks. At 24 hours after SCI, ATF4 and CHOP are upregulated in under perfused microvessels. We observed vascular protection 3 days post-SCI and a significant decrease in macrophage infiltration by the end of the first week. These results suggest that modulating ER-stress signaling in endothelial cells and macrophages may protect against vascular injury and attenuate inflammation post-SCI.

The cross-talk between autophagy and endoplasmic reticulum stress in blood-spinal cord barrier disruption after spinal cord injury

“…Excessive ER stress may lead to apoptosis by activating CHOP and Cleaved-Caspase12, resulting in secondary injury after SCI [12, 39]. Previous study has reported that following contusive SCI, CHOP deficiency in mice significantly preserves microvascular density and attenuated macrophage infiltration when compared to wild type mice [40]. Consistent with the prior study, our present study has also found that ER stress was significantly induced by SCI and 4-PBA treatment, a classical ER stress inhibitor, ameliorated the effect of SCI on BSCB permeability and the loss of AJ and TJ proteins, which also been found in a TG-treated HBMVEC model in vitro.…”

“…Autophagy is a lysosome-dependent essential cellular catabolic pathway that serves to degrade cytoplasmic proteins, protein aggregates and organelles [23, 41]. There are some evidences reported that moderate autophagy protect ECs against cell injury under stressful circumstances [24, 32, 42–45].…”

CD36 deletion improves recovery from spinal cord injury

“…CD36 activation induces apoptosis in endothelial cells (Jimenez et al, 2000), and we observed a decrease in vascular CHOP expression following injury in CD36 −/− mice. CHOP −/− mice exhibit improved vascular sparing and functional recovery following SCI (Fassbender et al, 2012; Ohri et al, 2011). Alternatively, CD36 −/− mice may exhibit an earlier angiogenic response following injury.…”

“…The decrease in heterodomain macrophages in CD36 −/− mice may therefore result from a combination of reduced chemokine release and defective macrophage chemotactic responses following SCI. CHOP −/− mice exhibit improved vascularity and reduced macrophage infiltration following injury (Fassbender et al, 2012). Lower ERSR-induced apoptosis in these mice may lead to less inflammation and reduced production of macrophage-recruiting chemokines.…”

“…Endothelial cells that cannot restore homeostasis induce expression of the pro-apoptotic proteins C/EBP (CCAAT enhancer binding protein) homologous protein (CHOP) and cation transport regulator-like protein 1 (CHAC-1) downstream of ATF4 (Mungrue et al, 2009). CHOP −/− mice exhibit a reduced inflammatory response, improved vascular sparing and enhanced locomotor recovery following SCI (Fassbender et al, 2012; Ohri et al, 2011). This improved vascular sparing coincides with a peak of lipid peroxidation, oxidative damage and accumulated protein adducts of 4HNE (Carrico et al, 2009), the most abundant unsaturated aldehyde generated in oxidized lipids by reactive oxygen species (Benedetti et al, 1980).…”