The Role of NF-κB in Neuroinflammation

Abstract—NF-κB is a family of nuclear transcription factors that play a leading role in the pathogenesis of many chronic inflammatory processes and in immune response regulation. At the end of the last century, NF-κB was mainly considered as a mediator of apoptosis in immune cells. Subsequent studies demonstrated its involvement in the development of the central nervous system, plasticity, neuronal differentiation, neurodegeneration, and brain injury. However, its role in the regulation of survival of mature CNS neurons in neuroinflammation proved controversial. This review summarizes the data on the involvement of NF-κB in the response of different brain cell types to the action of pro-inflammatory factors. Different subunits of the NF-κB family form dimers whose involvement in the regulation of gene expression depends on stimulus type. Interestingly, NF-κB is involved in the pro-inflammatory activation of microglia and astrocytes, whereas in neurons its protective or degenerative effects depend on the type of stimulus and on the time of the delayed cell response. The stimulus-dependent nature of NF-κB activation is determined by a wide range of receptors triggering a number of cell signaling cascades that terminate in the activation of the transcription factor. Tumor necrosis factor receptors (TNFR) or death receptors, Toll-like receptors (TLR), and protease-activated receptors (PAR) are among the membrane receptors capable of initiating intracellular cascades leading to the activation of NF-κB. Importantly, NF-κB activity and its effects can be modulated by other transcription factors. STAT1, STAT3, and Sirt1 are the molecules that, according to recent studies, are able to change the character of the NF-κB-mediated cellular responses. Thus, NF-κB is a transcription factor playing one of the key roles in determining the outcome of negative stimuli on the nervous system, which is why it may be considered as a pharmacological target for treating neurodegenerative processes associated with inflammation.