LCN2 Regulates Microglia Polarization Through the p38MAPK-PGC-1α-PPARγ Pathway to Alleviate Traumatic Brain Injury.

Abstract

Traumatic brain injury (TBI) is a common traumatic event that imposes a significant burden on families and society. Lipocalin (LCN) is a class of multifunctional secreted lipoprotein molecules. This study aimed to explore the role and possible mechanism of LCN2 in TBI. A rat model of TBI was constructed and adeno-associated virus-coated shRNA-LCN2 was used to silence LCN2 expression. The modified neurological severity score (mNSS), learning and memory ability, pathological injury of brain tissue, number of neurons, and expression of neurotrophic factors were analyzed, and the expression of inflammatory factors, M1/M2 polarization of microglia, and p38MAPK-PGC-1α-PPARγ pathway after LCN2 silencing were further detected. Results found that LCN2 was highly expressed in the brain tissue of TBI rats, and there were obvious learning and cognitive impairments and pathological injury of brain tissue. After silencing LCN2, the mNSS was further increased, and the learning and cognitive ability was weakened. Similarly, silencing LCN2 increased the brain tissue water content, aggravated the histopathology degree, decreased the number of surviving neurons, and reduced the expression of neurotrophic factors in TBI model rats. In addition, the expression of M1 proinflammatory cytokines and polarization markers in microglia of TBI was increased, and the expression of M2 cytokines and markers was decreased after silencing LCN2. Silencing LCN2 also inhibited the activation of the p38MAPK-PGC-1α-PPARγ pathway. In conclusion, LCN2 was released by surviving neurons after TBI, and the increased LCN2 activated the p38MAPK-PGC-1α-PPARγ pathway, which promoted M2 polarization of microglia, and secreted neurotrophic factors, thereby alleviating secondary brain injury.