What is nuclear factor-kB \((\mathrm{NF}-\mathrm{kB})\) ? Describe the status of \(\mathrm{NF}-\mathrm{kB}\) in normal brain cells. What are the possible signaling mechanisms for the activation of \(\mathbf{N F - \kappa B}\) ? How is the activation of NF-kB related to neuroinflammatory diseases like MS and meningitis?

Nuclear factor-kappa B (NF-kB) is a protein complex that regulates DNA transcription and ultimately affects the expression of various genes. It plays a crucial role in controlling the immune response to infection and regulates various cellular processes, including cell division, survival, and inflammation. It can be found in most cell types in vertebrates.

In normal brain cells, NF-kB exists in an inactive form in the cell cytoplasm, bound to molecules called inhibitors of kB (I-kB). In this state, it does not influence the transcription of target genes. Under non-stimulated conditions, NF-kB has little influence on the functioning of brain cells, allowing them to continue their routine activities.

There are two main signaling pathways that activate NF-kB: the canonical and non-canonical pathways. Both pathways involve the degradation of I-kB molecules. The canonical pathway: This activation is triggered by pro-inflammatory cytokines, bacterial products, or viral infections. Activation of this pathway leads to the activation of I-kB kinase (IKK) complex, phosphorylation, and ubiquitination of I-kB, releasing NF-kB and allowing it to enter the nucleus and modulate transcription. The non-canonical pathway: This pathway is activated by specific receptors such as BAFF-R, CD40, and LTβR. It involves the activation of NF-kB-inducing kinase (NIK) and subsequent phosphorylation of I-kB by IKKα, leading to the release and nuclear translocation of NF-kB.

Activation of NF-kB has been implicated as a key player in the development and progression of various neuroinflammatory disorders. In these diseases, the activation of NF-kB leads to the increased expression of pro-inflammatory genes, resulting in the exacerbation of neuroinflammation and neurodegeneration. This may lead to the recruitment of immune cells to the central nervous system, causing further activation of NF-kB and more escalation of inflammation.

In multiple sclerosis (MS), aberrant activation of NF-kB in immune cells and brain cells contribute to the production of pro-inflammatory cytokines, leading to the destruction of myelin, the insulating layer of the nerve fibers. In the case of meningitis, the activation of NF-kB in immune cells and the brain's endothelial cells promotes the production of inflammatory mediators that disrupt the blood-brain barrier, allowing the pathogen to invade the brain and cause inflammation. In summary, NF-kB is a critical regulator of immune response and inflammation, and its activation has been implicated in the development and progression of neuroinflammatory disorders like MS and meningitis. By understanding the mechanisms through which NF-kB operates, researchers can develop potential therapeutic strategies to target NF-kB pathways in the treatment of neuroinflammatory diseases.