Traumatic Brain Injury: Crosstalk Between ER and Mitochondria Contributes to Oligodendrocyte Cell Death and Demyelination

ObjectiveDemyelination is one of the manifestations of traumatic brain injury (TBI). Mechanisms underlying oligodendrocyte cell death in white matter lesions have not been fully studied. In the present study our focus is to investigate how the pro-inflammation contributes to the ER stress, mitochondrial protein alteration leading to oligodendrocyte cell death that aggravates demyelination in TBI.Methods Weight drop method was used to induce the TBI. Immunohistochemical studies were done to understand the role of pro-inflammation in activating ER-stress leading to cell death and demyelination. Proteomic analysis of mitochondria was done using 2D-gel electrophoresis. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) was used to identify the mitochondrial functional protein changes and their role in cell death causing demyelination. Remyelination was assessed by treating with teriflunomide (TF). Results Histopathology studies revealed the infiltration of activated macrophages leading to cytokines secretion which initiates ATF6 activation by releasing BiP, the endoplasmic reticulum (ER) chaperone binding protein and unfolded proteins at the site of ER lumen. Activated ER stress alters the mitochondrial functional proteins leading to oligodendrocyte cell death causing white matter lesions and demyelination. Treatment with TF inactivates the macrophages and reduces the cytokines secretion at the site of injury promoting recovery and remyelination. ConclusionOur findings confirm pro-inflammation activates the ER stress sensors. The cross-talk between ER and mitochondria leads to cell death followed by demyelination. TF acts as an anti-inflammatory drug promoting oligodendroglial precursor cells maturation for recovery and secretion of myelin.