Pathogenic Functions of Tumor Necrosis Factor Receptor-Associated Factor 6 Signaling Following Traumatic Brain Injury

Neuroinflammation contributes to delayed (secondary) neurodegeneration following traumatic brain injury (TBI). Tumor necrosis factor receptor-associated 6 (TRAF6) signaling may promote post-TBI neuroinflammation, thereby exacerbating secondary injury. This study investigated the pathogenic functions of TRAF6 TBI in vivo and vitro . A rat model was established by air pressure contusion while lipopolysaccharide (LPS) exposure used induce inflammatory-like responses cultured astrocytes. Model rats were examined for cell-specific expression TRAF6, NF-?B, phosphorylated (p)-NF-?B, MAPKs (ERK, JNK, p38), p-MAPKs, chemokines (CCL2 CXCL1), chemokine receptors (CCR2 CXCR2) immunofluorescence, RT-qPCR, western blotting, ELISA, apoptosis TUNEL staining, spatial cognition Morris water maze testing. These measurements compared between receiving intracerebral injections TRAF6-targeted RNAi vector (AAV9-TRAF6-RNAi), empty vector, MAPK/NF-?B inhibitors, or vehicle. Primary astrocytes stimulated with LPS siRNA control transfection, MAPKs, chemokine, receptor levels evaluated blotting ELISA. expressed mainly neurons injured cortex, peaking 3 days post-TBI. Knockdown AAV9-TRAF6-RNAi improved learning memory, decreased TUNEL-positive cell number downregulated p-NF-?B, p-ERK, p-JNK, p-p38, CCL2, CCR2, CXCL1, CXCR2 Inhibitors ERK, p38 significantly suppressed TBI. Furthermore, TRAF6-siRNA inhibited LPS-induced p38, CXCL1 upregulation Targeting TRAF6-MAPKs/NF-?B-chemokine pathways provide a novel therapeutic approach reducing neuroinflammation concomitant